Novel Coumarin Derivative Having Antitumor Activity

ABSTRACT

The present invention provides a compound represented by general formula (1) below or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein: X is selected from heteroaryl etc., Y 1  and Y 2  are selected from —N═ etc., Y 3  and Y 4  are selected from —CH═ etc., A is selected from sulfamide etc., R 1  is selected from hydrogen etc., and R 2  is selected from C 1-6  alkyl etc. The compound or salt has sufficiently high antitumor activity, and is useful in the treatment of cell proliferative disorders, particularly cancers. The present invention also provides a pharmaceutical composition containing the compound or salt as an active ingredient.

TECHNICAL FIELD

The present invention relates to a novel coumarin derivative havingantitumor activity, and to a pharmaceutical composition containing thesame as an active ingredient, particularly to a therapeutic agent for acell proliferative disorder.

BACKGROUND ART

It has already been revealed that coumarin derivatives, i.e., compoundswhich have a coumarin skeleton as a core structure, and in which theskeleton is derivatized at various positions, have differentpharmacological effects depending on the position at which a chemicalmodification occurs (Non-patent document 31). For example, warfarin,which has antithrombogenic activity, is well known as a drug having acoumarin skeleton (Non-patent document 1). Furthermore, coumarinderivatives which exert antitumor activity by acting on variousdifferent target proteins, or coumarin derivatives which inhibitproteins associated with antitumor activity have been obtained bychemical modification at different positions of the core structure.

A coumarin derivative that exerts antitumor activity by inhibitingsteroid sulfatase has been reported (Non-patent documents 2 to 6). Thisis currently in clinical testing. This compound forms a cycloalkyl groupat the 3- and 4-positions of the coumarin skeleton, and has a sulfamategroup at the 7-position. Its application to breast cancer is beingconsidered from the viewpoint of pharmacological action.

Furthermore, as for coumarin derivatives which exert antitumor activitythrough binding to the estrogen receptor, a group of compounds having acharacteristic substituent at the 4-position have been reported.Specifically, there have been reported a group of compounds having anarylalkyl group at the 4-position and having substituents at the 3- and7-positions (Patent document 1), and a group of compounds in which aphenyl group is directly bound to the skeleton at the 4-position, andwhich have a phenoxy group at the 3-position (Patent document 2).

Also, as for a coumarin derivative exhibiting Raf inhibitory activityand exhibiting antitumor activity in cells, a compound having a6-pyrazinyloxy group at the 7-position has been reported (Patentdocument 5).

In addition, known are several coumarin derivatives whose targetproteins are unknown, and which are reported to exhibit antitumoractivity. These include a group of compounds derived from naturalsources (Non-patent documents 7 to 12), and a group of new compoundsobtained by chemical synthesis (Non-patent documents 13 to 23, 32 to34). As for the new compounds obtained by chemical synthesis, there havebeen reported, for example: a compound having alkoxy groups at the 5-,6- and 7-positions of the coumarin skeleton (Non-patent document 13); acompound having an alkoxy group only at the 7-position of the coumarinskeleton (Non-patent document 14); a compound having an enone functionalgroup at the 6- or 7-position of the coumarin skeleton (Non-patentdocument 15); a compound having a methyl group at the 4-position of thecoumarin skeleton, and substituents at the 7- and 8-positions(Non-patent document 16); a compound having substituents at all of the4-, 5-, 6-, 7- and 8-positions of the coumarin skeleton (Non-patentdocument 17); a compound in which an amide group, ester group orsulfonamide group is directly bound to the coumarin skeleton at the3-position, and which has a substituent at the 6- or 8-position(Non-patent documents 18 and 19); a compound in which an amide group isdirectly bound to the coumarin skeleton at the 3-position, and which hasa substituent at the 7-position (Patent document 3 and Non-patentdocument 20); a compound having substituents at the 6- and 7-positionsof the coumarin skeleton (Non-patent document 21); a compound having ahydroxy group at the 7-position of the coumarin skeleton, and a nitrogroup at an appropriate position of the 3-, 6- and 8-positions(Non-patent documents 22 and 23); and a compound having a methoxy orhydroxy group at the 7-position of the coumarin skeleton, a phenyl groupat the 3-position, and a substituent at the 4-position.

There have also been reported: a compound having a substituent with anitrogen atom (diethylamino group, etc.) at the 7-position, a cyanogroup at the 4-position, and a heteroaryl group at the 3-position(optionally with no substituent at the 4-position) (Non-patent document32); and a compound having a heteroaryl group at the 3-position, and amethyl group, halogen atom, nitro group, etc. at the 6-, 7- or8-position (Non-patent document 33). There have also been reportedexamples of using a compound with a coumarin structure as a ligand for aPd compound having antitumor activity in cells (Non-patent document 34).

As for compounds which exhibit target protein inhibitory activity, andwhich are likely to have antitumor activity despite the absence of areport dealing with their antitumor activity, there have been reportedcoumarin derivatives exhibiting TNFα inhibitory activity (Patentdocument 4 and Non-patent documents 24 to 28), aromatase inhibitoryactivity (Non-patent document 29), MEK inhibitory activity (Non-patentdocument 30), or the like. In compounds mentioned in these reports, thesubstituents are located at the 3-, 4-, 6- or 7-position of the coumarinskeleton.

As described above, although several coumarin derivatives havingantitumor activity are known, few of the compounds exhibit asufficiently high antitumor activity to put it to practical use as ananticancer drug. Therefore, more practical compounds having sufficientlyhigh antitumor activity are still strongly sought.

Patent document 1: International Publication WO 2000/039120

Patent document 2: International Publication WO 2004/069820

Patent document 3: International Publication WO 2003/024950

Patent document 4: International Publication WO 2002/008217

Patent document 5: International Publication WO 2006/067466

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Non-patent document 3: Lloyd, M. D.; Pederick, R. L.; Natesh, R.; Woo,L. W. L.; Purohit, A.; Reed, M. J.; Acharya, K. R.; Potter, B. V. L.;Biochem. J. 2005, 385, 715-720

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Non-patent document 9: Chen, Y-C.; Cheng, M-J.; Lee, S-J.; Dixit, A-K.;Ishikawa, T.; Tsai, I-L.; Chen, I-S.; Hely. Chim. Acta 2004, 87,2805-2811

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Non-patent document 19: Reddy, N. S.; Gumireddy, K.; Mallireddigari, M.R.; Cosenza, S. C.; Venkatapuram, P.; Bell, S. C.; Reddy, E. P.; Reddy,M. V. R.; Bioorg. Med. Chem. 2005, 13, 3141-3147

Non-patent document 20: Kempen, I.; Papapostolou, D.; Thierry, N.;Pochet, L; Counerotte, S.; Masereel, B.; Foidart, J. M.; Ravaux, M. R.;Noeul, A.; Pirotte, B.; Br. J. Cancer 2003, 88, 1111-1118

Non-patent document 21: Kim, H. H.; Bang, S. S.; Ghoi, J. S.; Han, H.;Kim, I-H.; Cancer Letters 2005, 223, 191-201

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Non-patent document 24: Cheng, J. F.; Chen, M.; Wallace, D.; Tith, S.;Arrhenius, T.; Kashiwagi, H.; Ono, Y.; Ishikawa, A.; Sato, H.; Kozono,T.; Sato, H.; Nadzan, A. M.; Bioorg. Med. Chem. Lett. 2004, 14,2411-2415

Non-patent document 25: Fries, W.; Mazzon, E.; Sturiale, S.; Giofre, M.R.; Lo Presti, M. A.; Cuzzocrea, S.; Campo, G. M.; Caputi, A. P.; Longo,G.; Sturniolo, G. C.; Life Sci. 2004, 74, 2749-2756

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DISCLOSURE OF THE INVENTION

The object of the present invention is to provide a compound which hassufficiently high antitumor activity and which is useful as atherapeutic agent for a cell proliferative disorder, particularlycancer, and a pharmaceutical composition containing the compound as anactive ingredient.

The inventors of the present invention conducted intensive research forthe purpose of providing a novel compound effective for treatment of acell proliferative disorder, particularly cancer, and found that acoumarin derivative which has substituents at the 3-, 4- and 7-positionsof the coumarin skeleton, which may have a substituent at the6-position, and which has a sulfamide group or α-amidomethylenesulfonamide group, is a compound which has high antitumor activity, orwhich has high antitumor activity and exhibits high systemic exposure.The present invention was completed on the basis of this finding.

The present invention provides a compound represented by general formula(11) below or a pharmaceutically acceptable salt thereof:

wherein:

G¹, G², G³ and G⁸ are each independently —N═, —CR¹═ or —C(-G⁹-X)═;

one from among G¹, G², G³ and G⁸ is —C(-G⁹-X)═;

X is a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally besubstituted with a group selected from a halogen atom, a hydroxy group,a cyano group and —NR⁵⁶R⁵⁷), an aryl group, a heterocyclic group,R³¹CS—, R³¹CO—, R³³R³⁴NCS—, R³³R³⁴NC═NH—, R³R⁴NCO— or R³³R³⁴NCO₂—;

G⁹ is a single bond, an oxygen atom, a sulfur atom, —(CR³⁵R³⁶)₁— (where1 represents an integer of 1 to 3) or —NR³⁷—;

Ring G⁶ is a divalent aryl group or a divalent heterocyclic group,

A is a group represented by general formula (2) below or a grouprepresented by general formula (3) below:

G⁴ is an oxygen atom, a sulfur atom, —NR³⁸— or —CR⁴⁰R⁴¹—;

G⁵ is two hydrogen atoms, or an oxygen atom, a sulfur atom or ═CH₂;

G⁷ is an oxygen atom, —CR⁴²R⁴³—, —CR⁴²R⁴³—O—, —O—CR⁴²R⁴³—, —CONR⁴⁴—,—NR⁴⁴CO—, —NR⁴⁵—, —NR⁴⁵CR⁴²R⁴³—, —CR⁴²R⁴³NR⁴⁵—, —S(═O)_(n)—,—NR⁴⁴S(═O)_(n)—, —S(═O)_(n)NR⁴⁴— (where n represents an integer of 0 to2), —N═CR⁴²—, —CR⁴²═N—, —CR⁴²═CR⁴³—, —≡C—, —NR⁴⁴—O—, —O—NR⁴⁴—, —C(═O)—O—or —O—C(═O)—;

R¹ is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkyl group(where the C₁₋₆ alkyl group may optionally be substituted with a groupselected from a halogen atom, a hydroxy group and —NR⁴⁶R⁴⁷), a C₂₋₇alkenyl group, a carbamoyl group or a C₂₋₇ alkynyl group (where the C₂₋₇alkynyl group may optionally be substituted with a C₁₋₄ acyl group);

when G² or G³ is —CR¹═, G⁸ is —C(-G⁹-X)═, and X is R³R⁴NCO—,R³³R³⁴NC═NH— or R³³R³⁴NCS—; when G⁸ is —CR¹═, G³ is —C(-G⁹-X)═, and X isR³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; when G¹ or G⁸ is —CR¹═, G² is—C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; or when G² is—CR¹═, G¹ is —C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—,R¹ may form a single bond or —CH₂— together with R⁴ or R³⁴;

R² is a hydroxy group, a C₁₋₆ alkoxy group, —NR⁴⁸R⁴⁹ or a C₁₋₆ alkylgroup (where the C₁₋₆ alkyl group may optionally be substituted with agroup selected from a halogen atom, a hydroxy group, a C₁₋₆ alkoxygroup, a formyl group, —CO₂R⁵⁰ and —CO₂NR⁵¹R⁵²);

R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, R³¹, R⁴⁶ and R⁴⁷ are each independently ahydrogen atom, a C₁₋₆ alkoxy group, a C₃₋₈ cycloalkyl group or a C₁₋₆alkyl group (where the C₁₋₆ alkyl group may optionally be substitutedwith a group selected from a cyano group, a halogen atom, a hydroxygroup, a C₁₋₆ alkoxy group, —NR¹³R¹⁴, —CONR²⁸R²⁹ and an aryl group);

R³³ and R³⁴ are each independently a hydrogen atom, a C₁₋₆ alkyl groupor an aryl group;

the combination of R³ and R⁴, combination of R⁶ and R⁷, combination ofR⁹ and R¹⁰, combination of R³³ and R³⁴, and combination of R⁴⁶ and R⁴⁷may form, together with the nitrogen atom to which they are bonded, a 4-to 6-membered heterocyclic group having at least one nitrogen atom(where the heterocyclic group may optionally be fused with a benzenering);

one R³⁵ group and one R³⁶ group are each independently a hydrogen atom,a halogen atom or a C₁₋₆ alkyl group;

R⁴⁵ is a hydrogen atom, a C₁₋₆ alkyl group or —S(═O)_(m)NR⁵⁴R⁵⁵ (where mrepresents an integer of 0 to 2);

R¹³, R¹⁴, R⁵⁶ and R⁵⁷ are each independently a hydrogen atom, a C₁₋₆alkyl group, —COR³² or —CO₂R³²; and

R⁵, R⁸, R²⁸, R²⁹, R³², R³⁷, R³⁸, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁸, R⁴⁹, R⁵⁰,R⁵¹, R⁵², R⁵⁴ and R⁵⁵ are each independently a hydrogen atom or a C₁₋₆alkyl group.

G¹, G² and G³ are each independently preferably —CR¹═, and G¹ and G³ aremore preferably —CH═.

G⁸ is preferably —C(-G⁹-X)═. The following groups may be mentioned asexamples of X-G⁹-:

When G² or G³ is —CR¹═, G⁸ is —C(-G⁹-X)═, and X is R³R⁴NCO—,R³³R³⁴NC═NH— or R³³R³⁴NCS—; when G⁸ is —CR¹═, G³ is —C(-G⁹-X)═, and X isR³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; when G¹ or G⁸ is —CR¹═, G² is—C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; or when G² is—CR¹═, G¹ is —C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—,R¹ may form a single bond or —CH₂— together with R⁴ or R³⁴.

The following partial structures may be mentioned as examples of partialstructures formed when R¹ and R⁴ are linked:

More specifically, the following partial structures may be mentioned:

[where the combinations of G⁹, Z⁴, R³, G¹ and G³ are as listed in thetable below.]

G⁹ Z⁴ R³ G¹ G³ O O CH₃ CH CH O O H CH CH S O CH₃ CH CH O S CH₃ CH CH NHO CH₃ CH CH O O CH₃ N CH[where the combinations of G⁹, Z³, R³, G¹ and G² are as listed in thetable below.]

G⁹ Z³ R³ G¹ G² O O CH₃ CH CH O O H CH CH S O CH₃ CH CCH₃ O S CH₃ CH CHNH O CH₃ CH CF O O CH₃ N CH O O CH₃ CH N

When G⁹ is —(CR³⁵R³⁶)₁— (where 1 represents an integer of 1 to 3), X ispreferably R³³R³⁴NCO₂—.

When X is a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionallybe substituted with a group selected from a halogen atom, a hydroxygroup, a cyano group and —NR⁵⁶R⁵⁷) and G⁹ is a single bond, R¹ ispreferably a hydrogen atom, a halogen atom, a cyano group, a C₂₋₇alkenyl group, a carbamoyl group or a C₂₋₇ alkynyl group (where theC₂₋₇alkynyl group may optionally be substituted with a C₁₋₄ acyl group).

The compound represented by general formula (11) is preferably acompound represented by general formula (1) below:

wherein:

X is a heteroaryl group or R³R⁴NCO—;

Y¹ and Y² are each independently —N═ or —CR¹═;

Y³ and Y⁴ may be the same or different, and are each —CR¹²═;

A is a group represented by general formula (2) below or a grouprepresented by general formula (3) below:

R¹ is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkylgroup, a C₂₋₇ alkenyl group, a carbamoyl group or a C₂₋₇ alkynyl group(where the C₂₋₇ alkynyl group may optionally be substituted with a C₁₋₄acyl group);

R² is a C₁₋₆ alkyl group optionally substituted with a halogen atom;

R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ are each independently a hydrogen atom, aC₁₋₆ alkoxy group, a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group (wherethe C₁₋₆ alkyl group may optionally be substituted with a group selectedfrom a cyano group, a halogen atom, a hydroxy group, a C₁₋₆ alkoxy groupand —NR¹³R¹⁴);

the combination of R³ and R⁴, combination of R⁶ and R⁷, and combinationof R⁹ and R¹⁰ may form, together with the nitrogen atom to which theyare bonded, a 4- to 6-membered heterocyclic group having at least onenitrogen atom;

R⁵, R⁸, R¹³ and R¹⁴ are each independently a hydrogen atom or a C₁₋₆alkyl group;

R¹¹ is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₄ acylgroup, a C₁₋₄ ac lox group or —NR¹⁵R¹⁶;

R¹² is a hydrogen atom, a halogen atom or a C₁₋₆ alkyl group; and

R¹⁵ and R¹⁶ are each independently a hydrogen atom or a C₁₋₄ acyl group.

The above described compound or a pharmaceutically acceptable saltthereof has more excellent properties as an anticancer drug thanconventional coumarin compounds, because it has markedly high antitumoractivity compared to conventional compounds, or because it hassufficiently high antitumor activity that is equivalent to those ofconventional compounds, and exhibits higher systemic exposure thanconventional compounds.

The above described compound or a pharmaceutically acceptable saltthereof having such properties can be used as an active ingredient of apharmaceutical composition. Therefore, the present invention alsoprovides a pharmaceutical composition comprising a compound representedby general formula (11), preferably general formula (1), or apharmaceutically acceptable salt thereof as an active ingredient.

Further, the above described compound or a pharmaceutically acceptablesalt thereof can be used as an active ingredient of a therapeutic agentfor a cell proliferative disorder, particularly cancer. Therefore, thepresent invention also provides a therapeutic agent for a cellproliferative disorder, particularly cancer, comprising a compoundrepresented by general formula (11), preferably general formula (1), ora pharmaceutically acceptable salt thereof as an active ingredient.

According to the present invention, there are provided a compound whichhas sufficiently high antitumor activity, and is useful in the treatmentof cell proliferative disorders, particularly cancers, and apharmaceutical composition comprising the compound as an activeingredient.

BEST MODES FOR CARRYING OUT THE INVENTION

Preferred embodiments of the present invention will now be describedbelow.

The compound of the present invention is represented by general formula(11) above, preferably general formula (1) above.

In general formulas (11) and (1), the heteroaryl group means a 5- to10-membered aromatic heterocyclic group having one or more heteroatomsselected from oxygen, nitrogen and sulfur atoms. As specific examples,there may be mentioned furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl,benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl,isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, indolizinyl and imidazopyridyl, among which thiazolyl,pyrimidinyl, pyridyl and the like are preferred, and thiazol-2-yl,pyrimidin-2-yl, 2-pyridyl and the like are further preferred.

The heteroaryl group may be optionally substituted with halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C₂₋₇alkenyl, C₂₋₇ alkynyl or the like on an atom of the ring, but it ispreferably unsubstituted.

The aryl group means an aromatic hydrocarbon group having 6 to 10 carbonatoms. As specific examples, there may be mentioned phenyl, 1-naphthyland 2-naphthyl. The aryl group may be optionally substituted withhalogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, amino, carbamoyl, nitro,carboxy, C₂₋₇ alkenyl, C₂₋₇ alkynyl or the like on a carbon atom.

The divalent aryl group means a group obtained by removing any one ofthe hydrogen atoms on the atoms of the aforementioned aryl group. Thedivalent aryl group may be substituted with G⁷ and A in any manner, andwhen the divalent aryl group is a phenylene group, for example, they maybe 1,2-substituted, 1,3-substituted or 1,4-substituted.

The halogen atom means a fluorine, chlorine, bromine or iodine atom.

The C₁₋₆ alkyl group means a straight- or branched-chain alkyl grouphaving 1 to 6 carbon atoms. As specific examples, there may be mentionedmethyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl,1-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyland 2-ethylbutyl.

The C₂₋₇ alkenyl group means a straight- or branched-chain alkenyl grouphaving 2 to 7 carbon atoms. As specific examples, there may be mentionedvinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl,hexenyl, hexadienyl, heptenyl, heptadienyl and heptatrienyl.

The C₂₋₇ alkynyl group means a straight- or branched-chain alkynyl grouphaving 2 to 7 carbon atoms. As specific examples, there may be mentionedethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butyryl, 3-butynyl,pentynyl, pentadiynyl, hexynyl, hexadiynyl, heptynyl, heptadiynyl andheptatriynyl.

The C₁₋₄ acyl group means an acyl group having 1 to 4 carbon atoms. Asspecific examples, there may be mentioned formyl, acetyl, n-propionyl,i-propionyl, butyryl and sec-butyryl (isobutyryl).

The C₁₋₆ alkoxy group means an alkyloxy group having, as an alkylmoiety, a straight- or branched-chain alkyl group having 1 to 6 carbonatoms. As specific examples, there may be mentioned methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy and hexoxy.

The C₃₋₈ cycloalkyl group means a 3- to 8-membered cyclic alkyl groupwhich has 3 to 8 total carbon atoms (where the cyclic alkyl group mayoptionally be substituted with a straight- or branched-chain alkyl grouphaving 1 to 3 carbon atoms). As specific examples, there may bementioned: nonsubstituted cycloalkyl groups such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; andsubstituted cycloalkyl groups such as methylcyclopropyl,ethylcyclopropyl, dimethylcyclopropyl, trimethylcyclopropyl,diethylcyclopropyl, ethylmethylcyclopropyl, dimethylethylcyclopropyl,diethylmethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl,dimethylcyclobutyl, trimethylcyclobutyl, tetramethylcyclobutyl,diethylcyclobutyl, ethylmethylcyclobutyl, dimethylethylcyclobutyl,methylcyclopentyl, ethylcyclopentyl, dimethylcyclopentyl,trimethylcyclopentyl, ethylmethylcyclopentyl, methylcyclohexyl,ethylcyclohexyl, dimethylcyclohexyl and methylheptyl, among whichnonsubstituted cycloalkyl groups are preferred, and cyclopropyl isfurther preferred.

The 4- to 6-membered heterocyclic group having at least one nitrogenatom means a saturated or unsaturated heterocyclic group which has 4 to6 ring atoms and which may have, in addition to one or more nitrogenatoms, one or more heteroatoms selected from oxygen and sulfur atoms(where the heterocyclic group may optionally be fused with a benzenering). As specific examples, there may be mentioned azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, dihydropyrrolyl,imidazolyl, imidazolynyl, imidazolidinyl, pyrazolyl, pyrazolynyl,pyridazolidinyl, oxazolynyl, oxazolidinyl, morpholinyl, thiomorpholinyl,pyridinyl, dihydropyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl.

The 4- to 6-membered heterocyclic group having at least one nitrogenatom may be optionally substituted with halogen, C₁₋₆ alkyl, C₁₋₆alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C₂₋₇ alkenyl, C₂₋₇alkynyl or the like on an atom of the ring.

The heterocyclic group means a 4- to 12-membered, preferably 5- to7-membered, saturated or unsaturated cyclic group having one or moreheteroatoms selected from nitrogen, oxygen and sulfur atoms. Theheterocycle may be a monocycle or fused ring, and examples thereofinclude the aforementioned heteroaryl groups as well as theaforementioned 4- to 6-membered heterocyclic groups having one or morenitrogen atoms.

As specific examples of the heterocyclic group, there may be mentioned:furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl,indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, indolizinyl, imidazopyridyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, pyrrolyl, dihydropyrrolyl, imidazolyl,imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyridazolidinyl,oxazolinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, pyridinyl,dihydropyridinyl, pyrimidinyl, pyridazinyl, tetrahydrofuryl,tetrahydrothienyl, dioxolanyl, oxathiolanyl, dioxanyl, isobenzofuranyl,chromenyl, indolizinyl, indolyl, isoindolyl, indazolyl, puryl,quinolidinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthylidinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl,chromanyl, quinuclidinyl, oxacycloheptyl, dioxacycloheptyl,thiacycloheptyl and diazacycloheptyl.

The heterocyclic group may be optionally substituted with halogen, C₁₋₆alkyl, C₁₋₆ alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C₂₋₇alkenyl, C₂₋₇ alkynyl or the like on an atom of the ring.

The divalent heterocyclic group means a group obtained by removing anyone of the hydrogen atoms on the atoms of the aforementionedheterocyclic group. The divalent heterocyclic group may be substitutedwith G⁷ and A in any manner, and when the divalent heterocyclic group ispyridinediyl, for example, they may be 2,3-substituted, 2,4-substituted,2,5-substituted, 2,6-substituted, 3,4-substituted, 3,5-substituted,3,6-substituted, 4,5-substituted, 4,6-substituted or 5,6-substituted.

The C₁₋₄ acyloxy group means an acyloxy group having, as an acyl moiety,an acyl group having 1 to 4 carbon atoms. As specific examples, theremay be mentioned formyloxy, acetyloxy, n-propionyloxy, i-propionyloxy,butyryloxy and sec-butyryloxy (isobutyryloxy).

As specific examples of the C₁₋₆ alkyl group substituted with a halogenatom, there may be mentioned fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl,pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl,heptafluoropropyl, fluorobutyl, difluorobutyl, trifluorobutyl,fluoropentyl, difluoropentyl, trifluoropentyl, tetrafluoropentyl,fluoroheptyl, difluoroheptyl, trifluoroheptyl, tetrafluoroheptyI,pentafluoroheptyl, chloromethyl, dichloromethyl, trichloromethyl,chloroethyl, dichloroethyl, trichloroethyl, pentachloroethyl,chloropropyl, dichloropropyl, trichloropropyl, heptachloropropyl,chlorobutyl, dichlorobutyl, trichlorobutyl, chloropentyl,dichloropentyl, trichloropentyl, tetrachloropentyl, chloroheptyl,dichloroheptyl, trichloroheptyl, tetrachloroheptyl, pentachloroheptyl,bromomethyl, dibromomethyl, tribromomethyl, bromoethyl, dibromoethyl,tribromoethyl, pentabromoethyl, bromopropyl, dibromopropyl,tribromopropyl, heptabromopropyl, bromobutyl, dibromobutyl,tribromobutyl, bromopentyl, dibromopentyl, tribromopentyl,tetrabromopentyl, bromoheptyl, dibromoheptyl, tribromoheptyl,tetrabromoheptyl, pentabromoheptyl, iodomethyl, diiodomethyl,triiodomethyl, iodoethyl, diiodoethyl, triiodoethyl, pentaiodoethyl,iodopropyl, diiodopropyl, triiodopropyl, heptaiodopropyl, iodobutyl,diiodobutyl, triiodobutyl, iodopentyl, diiodopentyl, triiodopentyl,tetraiodopentyl, iodoheptyl, diiodoheptyl, triiodoheptyl,tetraiodoheptyl and pentaiodoheptyl.

As for R¹, hydrogen, halogen, cyano, C₁₋₆ alkyl, carbamoyl, and C₂₋₇alkynyl (where the C₂₋₇ alkynyl may optionally be substituted with C₁₋₄acyl) are preferred; hydrogen, halogen, cyano, methyl, ethenyl andacetylethenyl are particularly preferred; hydrogen, halogen and methylare further preferred; and hydrogen, fluorine, chlorine and methyl arestill further preferred.

As for R², C₁₋₆ alkyl optionally substituted with fluorine is preferred;methyl, ethyl, n-propyl, fluoromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 1-fluoro-n-propyl, 2-fluoro-n-propyl and2,2-difluoro-n-propyl are particularly preferred; and —CH₃, —CH₂F and—CH₂CH₃ are further preferred.

R³, R⁴, R⁶, R⁷, R⁹ R and R¹⁰ are each preferably hydrogen or C₁₋₆ alkyl.As for the C₁₋₆ alkyl, methyl, ethyl, n-propyl and i-propyl arepreferred, and methyl, ethyl and i-propyl are particularly preferred.

R³ and R⁴ are each preferably a C₁₋₆ alkyl group. It is furtherpreferred that both R³ and R⁴ are the same C₁₋₆ alkyl group,particularly a methyl group.

R⁶ and R⁷ are each preferably hydrogen, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, orC₁₋₆ alkyl (where the C₁₋₆ alkyl may optionally be substituted with agroup selected from cyano, halogen, hydroxy, C₁₋₆ alkoxy and —NR¹³R¹⁴).As for the C₁₋₆ alkoxy represented by R⁶ or R⁷, methoxy and ethoxy arepreferred, and methoxy is particularly preferred. As for the C₃₋₈cycloalkyl represented by R⁶ or R⁷, nonsubstituted cycloalkyl ispreferred, and cyclopropyl is particularly preferred. As for the C₁₋₆alkyl represented by R⁶ or R⁷, methyl, ethyl and n-propyl are preferred,while ethyl is particularly preferred when the C₁₋₆ alkyl issubstituted, and methyl is particularly preferred when the C₁₋₆ alkyl isunsubstituted. The halogen atom to be selected as a substituent of theC₁₋₆ alkyl is preferably fluorine. The C₁₋₆ alkoxy to be selected as asubstituent of the C₁₋₆ alkyl is preferably methoxy.

As for R⁶ and R⁷, each one is more preferably hydrogen, nonsubstitutedcycloalkyl or nonsubstituted C₁₋₆ alkyl. As for the combination of R⁶and R⁷, combinations of: hydrogen atoms; hydrogen and methyl; hydrogenand cyclopropyl; methyl groups; hydrogen and cyanoethyl; hydrogen andmethoxyethyl; hydrogen and aminoethyl; hydrogen and trifluoroethyl;hydrogen and methoxy; hydrogen and hydroxyethyl; and hydrogen andmethylaminoethyl are preferred, and combinations of: hydrogen atoms;hydrogen and cyclopropyl; and hydrogen and methyl are particularlypreferred.

R⁹ and R¹⁰ are each preferably hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy. Asfor the C₁₋₆ alkyl, methyl, ethyl, n-propyl and i-propyl are preferred,and methyl, ethyl and i-propyl are particularly preferred. As for theC₁₋₆ alkoxy, methoxy, ethoxy, n-propoxy and i-propoxy are preferred, andmethoxy is particularly preferred.

As for the combination of R⁹ and R¹⁰, combinations of: hydrogen atoms;hydrogen and methyl; methyl groups; hydrogen and ethyl; ethyl groups;hydrogen and i-propyl; methyl and i-propyl; ethyl and i-propyl; i-propylgroups; hydrogen and methoxy; methyl and methoxy; ethyl and methoxy; andi-propyl and methoxy are preferred, and combinations of: hydrogen atoms;hydrogen and methyl; methyl groups; hydrogen and ethyl; hydrogen andi-propyl; and hydrogen and methoxy are particularly preferred.

R⁵ and R⁸ are preferably a hydrogen atom.

As for the C₁₋₄ acyl represented by R¹⁵ or R¹⁶, formyl, acetyl andpropionyl are preferred, and acetyl is particularly preferred. As forthe combination of R¹⁵ and R¹⁶, combinations of: hydrogen atoms; andhydrogen and acetyl are preferred, and a combination of hydrogen andacetyl is particularly preferred.

As for the C₁₋₆ alkyl represented by R¹¹, methyl, ethyl and n-propyl arepreferred, and methyl is particularly preferred. As the C₁₋₄ acylrepresented by R¹¹, formyl, acetyl and n-propionyl are preferred, andacetyl is particularly preferred. As the C₁₋₄ acyloxy represented byR¹¹, formyloxy, acetyloxy and n-propionyloxy are preferred, andacetyloxy is particularly preferred. As for R¹¹, hydrogen and halogenare preferred, and hydrogen and fluorine are particularly preferred.

As for Y¹, —N═, —CH═, —CF═ and —CCl═ are preferred; —N═, —CH═ and —CF═are particularly preferred; and —N═ and —CH═ are further preferred.

As for R¹¹ of —CR¹¹═ represented by Y², hydrogen, halogen, C₁₋₄ acyl and—NR¹⁵R¹⁶ are preferred, and hydrogen, fluorine and chlorine, acetyl and—NHCOCH₃ are particularly preferred. As for Y², —N═, —CH═ and —CF═ arepreferred, and —CH═ and —CF═ are particularly preferred.

As for R¹², hydrogen, fluorine and methyl are preferred; hydrogen andfluorine are particularly preferred; and hydrogen is further preferred.

R¹³ and R¹⁴ are each preferably hydrogen, methyl or ethyl, and morepreferably hydrogen or methyl. As for the combination of R¹³ and R¹⁴,combinations of hydrogen atoms; and hydrogen and methyl are preferred.

As for X, thiazol-2-yl, pyrimidin-2-yl, 2-pyridyl and R³R⁴NCO— (where R³and R⁴ have the same definitions as above) are preferred. It isparticularly preferred that both R³ and R⁴ are a methyl group.

A is preferably a group represented by general formula (2).

When X is a thiazol-2-yl group, it is preferred that: Y¹ is —N═ or —CH═;Y² is —CH═, —CF═ or —CCl═; R¹ is hydrogen, chlorine or methyl; and R² ismethyl, ethyl or fluoromethyl. Then, if A is a group represented bygeneral formula (2), the combination of R⁶ and R⁷ is preferably acombination of: hydrogen atoms; or hydrogen and methyl, and if A is agroup represented by general formula (3), the combination of R⁹ and R¹⁰is preferably a combination of: hydrogen and methyl; or hydrogen andcyclopropyl.

When X is a pyrimidin-2-yl group, it is preferred that: Y¹ is —N═ or—CH═; Y² is —N═, —CH═ or —CF═; R¹ is hydrogen, fluorine, chlorine ormethyl; R² is methyl, ethyl or fluoromethyl; A is a group represented bygeneral formula (2); and the combination of R⁶ and R⁷ is a combinationof hydrogen atoms, a combination of methyl groups, a combination ofhydrogen and methyl, or a combination of hydrogen and cyclopropyl.

When X is (H₃C)₂NCO—, it is preferred that: Y¹ is —N═ or —CH═; Y² is—CH═, —CF═ or —CCl═; R¹ is hydrogen, fluorine, chlorine, iodine, cyanoor methyl; and R² is methyl or fluoromethyl. Then, if A is a grouprepresented by general formula (2), the combination of R⁶ and R⁷ ispreferably a combination of: hydrogen atoms; hydrogen and methyl; ormethyl groups, and if A is a group represented by general formula (3),the combination of R⁹ and R¹⁰ is preferably a combination of: hydrogenand methyl; hydrogen and methoxyethyl; or hydrogen and cyanoethyl.

When Y¹ is —N═, it is preferred that: X is thiazol-2-yl, pyrimidin-2-ylor (H₃C)₂NCO—; Y² is —CH═, —CF═ or —CCl═; R¹ is hydrogen, fluorine,chlorine or methyl; R² is methyl or ethyl; A is a group represented bygeneral formula (2); and the combination of R⁶ and R⁷ is a combinationof hydrogen atoms, a combination of methyl groups, a combination ofhydrogen and methyl, or a combination of hydrogen and cyclopropyl.

When Y¹ is —CH═, it is preferred that: X is thiazol-2-yl, pyrimidin-2-ylor (H₃C)₂NCO—; Y² is —N═, —CH═ or —CF═; R¹ is hydrogen, fluorine,chlorine, iodine, methyl or cyano; and R² is methyl or fluoromethyl.Then, if A is a group represented by general formula (2), thecombination of R⁶ and R⁷ is preferably a combination of: hydrogen atoms;methyl groups; or hydrogen and methyl, and if A is a group representedby general formula (3), the combination of R⁹ and R¹⁰ is preferably acombination of: hydrogen and methyl; hydrogen and methoxyethyl; orhydrogen and cyanoethyl.

When Y² is —CH═, it is preferred that: X is thiazol-2-yl, pyrimidin-2-ylor (H₃C)₂NCO—; Y¹ is —N═ or —CH═; R¹ is hydrogen, fluorine, chlorine,iodine, methyl or cyano; and R² is methyl, ethyl or fluoromethyl. Then,if A is a group represented by general formula (2), the combination ofR⁶ and R⁷ is preferably a combination of: hydrogen atoms; methyl groups;or hydrogen and methyl, and if A is a group represented by generalformula (3), the combination of R⁹ and R¹⁰ is preferably a combinationof: hydrogen and methyl; hydrogen and methoxyethyl; or hydrogen andcyanoethyl.

When Y² is —CF═, it is preferred that: X is thiazol-2-yl, pyrimidin-2-ylor (H₃C)₂NCO—; Y¹ is —N═ or —CH═; R¹ is hydrogen, fluorine, chlorine ormethyl; R² is methyl, ethyl or fluoromethyl; A is a group represented bygeneral formula (2); and the combination of R⁶ and R⁷ is a combinationof hydrogen atoms, a combination of hydrogen and methyl, or acombination of hydrogen and cyclopropyl.

When R¹ is a hydrogen atom, it is preferred that: X is thiazol-2-yl,pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —N═, —CH═ or—CF═; and R² is methyl or fluoromethyl. Then, if A is a grouprepresented by general formula (2), the combination of R⁶ and R⁷ ispreferably a combination of: hydrogen atoms; or hydrogen and methyl, andif A is a group represented by general formula (3), the combination ofR⁹ and R¹⁰ is preferably a combination of hydrogen and methyl.

When R¹ is a fluorine atom, it is preferred that: X is thiazol-2-yl,pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —N═, —CH═ or—CF═; R² is methyl; A is a group represented by general formula (2); andthe combination of R⁶ and R⁷ is a combination of hydrogen atoms, acombination of methyl groups, a combination of hydrogen and methyl, acombination of hydrogen and cyclopropyl, a combination of hydrogen andmethoxyethyl, or a combination of hydrogen and cyanoethyl.

When R¹ is a chlorine atom, it is preferred that: X is thiazol-2-yl,pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —CH═ or —CF═; andR² is methyl or trifluoromethyl. Then, if A is a group represented bygeneral formula (2), the combination of R⁶ and R⁷ is preferably acombination of: methyl groups; or hydrogen and methyl, and if A is agroup represented by general formula (3), the combination of R⁹ and R¹⁰is preferably a combination of: hydrogen and methyl; hydrogen andmethoxyethyl; or hydrogen and cyanoethyl.

When R¹ is a methyl group, it is preferred that: X is thiazol-2-yl,pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —CH═, —CF═ or—CCl═; R² is methyl, ethyl or trifluoromethyl; A is a group representedby general formula (2); and the combination of R⁶ and R⁷ is acombination of hydrogen and methyl.

When R² is a methyl group, it is preferred that: X is thiazol-2-yl,pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —N═, —CH═, —CF═or —CCl═; and R¹ is hydrogen, fluorine, chlorine, iodine, methyl orcyano. Then, if A is a group represented by general formula (2), thecombination of R⁶ and R⁷ is preferably a combination of: hydrogen atoms;methyl groups; hydrogen and methyl; or hydrogen and cyclopropyl, and ifA is a group represented by general formula (3), the combination of R⁹and R¹⁰ is preferably a combination of: hydrogen and methyl; hydrogenand methoxyethyl; or hydrogen and cyanoethyl.

When R² is an ethyl group, it is preferred that: X is thiazol-2-yl orpyrimidin-2-yl; Y¹ is —N═; Y² is —CF═; R¹ is methyl; A is a grouprepresented by general formula (2); and the combination of R⁶ and R⁷ isa combination of hydrogen and methyl.

When R² is a fluoromethyl group, it is preferred that: X isthiazol-2-yl, pyrimidin-2-yl or (H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is—N═, —CH═ or —CF═; R¹ is hydrogen, fluorine, chlorine or methyl; A is agroup represented by general formula (2); and the combination of R⁶ andR⁷ is a combination of hydrogen and methyl.

When the combination of R⁶ and R⁷ is a combination of hydrogen atoms, itis preferred that: X is thiazol-2-yl, pyrimidin-2-yl or (H₃C)₂NCO—; Y¹is —N═ or —CH═; Y² is —N═, —CH═ or —CF═; R¹ is hydrogen, fluorine,chlorine or iodine; and R² is methyl, fluoromethyl, or ethyl.

When the combination of R⁶ and R⁷ is a combination of methyl groups, itis preferred that: X is thiazol-2-yl, pyrimidin-2-yl or (H₃C)₂NCO—; Y¹is —N═ or —CH═; Y² is —N═, —CH═, —CF═ or —CCl═; R¹ is hydrogen,fluorine, chlorine or methyl; and R² is methyl, fluoromethyl or ethyl.

When the combination of R⁶ and R⁷ is a combination of hydrogen andmethyl, it is preferred that: X is thiazol-2-yl, pyrimidin-2-yl or(H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —N═, —CH═, —CF═ or —CCl═; R¹ ishydrogen, fluorine, chlorine, iodine, methyl or cyano; and R² is methyl,ethyl or fluoromethyl.

When the combination of R⁹ and R¹⁰ is a combination of hydrogen andmethyl, it is preferred that: X is thiazol-2-yl, pyrimidin-2-yl or(H₃C)₂NCO—; Y¹ is —N═ or —CH═; Y² is —CH═ or —CF═; R¹ is hydrogen orchlorine; and R² is methyl.

As preferred examples of the compound represented by general formula(11), preferably general formula (1), or a pharmaceutically acceptablesalt thereof, there may be mentioned, for example:

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid 3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-iodo-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-methyl-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylaminobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylaminobenzyl)-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-chloro-4-fluoromethyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-fluoro-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran,

3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid6-chloro-4-methyl-3-{3-(dimethylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

3-{2-fluoro-3-(dimethylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-(2-hydroxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-(2-methoxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-(2-aminoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester hydrochloride,

dimethylcarbamic acid3-(3-(N-(N′-methyl-2-aminoethyl)methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester hydrochloride,

dimethylcarbamic acid3-(3-(N-2,2,2-trifluoroethyl-sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-methoxysulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-carbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

2-{2-fluoro-3-[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide,

dimethylcarbamic acid3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

2-{2-fluoro-3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide,

3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(ethylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(isopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrazin-2-yloxy)-2-oxo-2H-1-benzopyran,and

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyridin-2-yloxy)-2-oxo-2H-1-benzopyran.

Preferred from the viewpoint of antitumor activity are compounds ofgeneral formula (1) wherein: X is a thiazol-2-yl group, a pyrimidin-2-ylgroup or (H₃C)₂NCO—; Y¹ is —CH═ or —N═; Y² is —CH═, —CF═ or —CCl—; Y³and Y⁴ are —CH═; A is —NHSO₂NR⁶⁰R⁷⁰ or —NHSO₂CH₂CONCH₃R⁹⁰ (where R⁶⁰ andR⁹⁰ are each independently a hydrogen atom or a methyl group, and R⁷⁰ isa hydrogen atom, a methyl group, or an ethyl group (where the ethylgroup may optionally be substituted with a substituent selected frommethoxy and cyano)); R¹ is a hydrogen atom, a fluorine atom, a chlorineatom, an iodine atom, a methyl group or a cyano group; and R² is —CH₃,—CH₂F or —CH₂CH₃.

As examples preferred from the viewpoint of antitumor activity, theremay be mentioned, for example:

dimethylcarbamic acid3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester,

3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid6-fluoro-4-methyl-3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-iodo-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-methyl-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid6-chloro-4-fluoromethyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid6-chloro-4-methyl-3-{3-(dimethylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-(N-(2-methoxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester,

dimethylcarbamic acid3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester, and

dimethylcarbamic acid3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester.

Preferred from the viewpoint of systemic exposure are compounds ofgeneral formula (1) wherein: X is a thiazol-2-yl group or apyrimidin-2-yl group; Y¹ is —CH═ or —N═; Y² is —CH═ or —CF═; Y³ and Y⁴are —CH═; A is —NHSO₂NHR⁶⁰ or —NHSO₂CH₂CONHCH₃ (where R⁶⁰ is a hydrogenatom or a methyl group); R¹ is a hydrogen atom, a fluorine atom or amethyl group; and R² is —CH₃ or —CH₂F.

As examples preferred from the viewpoint of systemic exposure, there maybe mentioned, for example:

3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-fluoro-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran,and

2-{2-fluoro-3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide.

There also exist compounds, other than the compound represented bygeneral formula (11), which, like the compound represented by generalformula (11), have sufficiently high antitumor activity, and are usefulas therapeutic agents for cell proliferative disorders, particularlycancers.

As examples of such compounds, there may be mentioned compounds having astructure similar to the compound of general formula (11), except thatin place of the partial structure:

they have a structure below:

There may also be mentioned compounds having a structure similar to thecompound of general formula (11), except that in place of the partialstructure:

they have a structure below:

There may further be mentioned compounds having a structure similar tothe compound of general formula (11), except that in place of thepartial structure:

they have a structure below:

[where the combinations of G⁹, Z⁷, Z⁸, G¹ and G³ are as listed in thetable below.]

G⁹ Z⁷ Z⁸ G¹ G³ O N(CH₃)₂ N CH CH S N(CH₃)₂ N CH CH NH N(CH₃)₂ N CH CH ON(CH₃)₂ CH CH CH[where the combinations of G⁹, Z⁵, Z⁶, G¹ and G² are as listed in thetable below.]

G⁹ Z⁵ Z⁶ G¹ G² O N(CH₃)₂ N CH CCH₃ S N(CH₃)₂ N CH CH NH N(CH₃)₂ N CH CFO N(CH₃)₂ CH CH CH O N(CH₃)₂ N CH N S N(CH₃)₂ N N CH[where the combinations of G⁹, Z¹¹, Z¹², G¹ and G³ are as listed in thetable below.]

G⁹ Z¹¹ Z¹² G¹ G³ O N(CH₃)₂ N CH CH S N(CH₃)₂ N CH CH O N(CH₃)₂ CH CH CHNH N(CH₃)₂ N CH CH[where the combinations of G⁹, Z⁹, Z¹⁰, G¹ and G² are as listed in thetable below.]

G⁹ Z⁹ Z¹⁰ G¹ G² O N(CH₃)₂ N CH CH S N(CH₃)₂ N CH CH O N(CH₃)₂ CH CH CHNH N(CH₃)₂ N CH CH

A may be selected from groups represented by general formulas (2) and(3) above, as well as from groups represented by the following formulas:

[where * represents the position at which G⁶ is bonded.]

When A is a group represented by general formula (2), R⁷ may form a ringtogether with atoms of ring G⁶. As specific examples of partialstructures formed in such cases, there may be mentioned partialstructures represented by the following formulas:

[where * represents the position at which G⁷ is bonded.]

More specifically, the following partial structures may be mentioned:

[where * represents the position at which G⁷ is bonded, and thecombinations of Y¹, Y³, Y⁴ and Z² are as listed in the table below.]

Y¹ Y³ Y⁴ Z² CH CH CH NH CF CH CH NCH₃ CH CH CH CH₂ CF CH CH N(CH₃)CH₂ CHCH CH N(CH₃)CH₂CH₂ CH CH CH CH₂CH₂ CH CH CH CH₂CH₂CH₂ CF CH CH NH CH CHN NCH₃[where * represents the position at which G⁷ is bonded, and thecombinations of Y¹, Y³, Y⁴ and Z¹ are as listed in the table below.]

Y¹ Y³ Y⁴ Z¹ CH CH CH NH N CH CH NCH₃ CH CH CH CH₂ N CH CH N(CH₃)CH₂ CHCH CH N(CH₃)CH₂CH₂ CH CH CH CH₂CH₂ CH CH CH CH₂CH₂CH₂ N CH CH NH N CH NNCH₃

As specific examples of the compound represented by general formula(11), there may be mentioned compounds represented by the followingformulas:

[where the combinations of G⁹, Y¹, Y², Y³, Y⁴, G¹, G², G³, NR⁶R⁷, G⁷,and R² are as listed in the table below.]

X G⁹ Y¹ Y² Y³ Y⁴ G¹ G² G³ NR⁶R⁷ G⁷ R² (CH₃)₂NCO O N CF CH CH CH N CHN(CH₃)₂ CH₂ CH₃ (CH₃)₂NCO O CH CF CH CH N CH CH NH₂ CH₂ CH₃ 2-N-Methyl OCH CF CH CH CH N CH NH₂ CH₂ CH₃ imidazolyl (CH₃)₂NCO O CH CF N CH CH CHCH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CF CH N CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCOO N N CH CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CF CH CH N CH CH NHCH₃CH₂ CH₃ (CH₃)₂NCO O CH CF CH CH CH N CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O N CFCH CH N CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO NH N CF CH CH CH CH CH NHCH₃ CH₂CH₃ 2-Pyrimidinyl O CH CH N N CH CCH₃ CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O NCF CH CH N CH CH NHCH₃ CH₂ CH₂CH₃ 2-Pyrimidinyl O CH CF CH CH CH N CHNHCH₃ CH₂ CH₃ 2-Pyrimidinyl O N N CH CH CH N CH NHCH₃ CH₂ CH₂F2-Pyrimidinyl CH₂ CH CF CH CH CH CH CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O N CFCH CH CH N CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O CH CF CH CH CH N N NHCH₃ CH₂CH₃ 2-Thiazolyl O CH CH N CH CH CF CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O N CFCH CH CH CH CH NHCH₃ SO CH₃ 2-Thiazolyl CF₂ N CF CH CH N CH CH NHCH₃ SOCH₃ 2-N-Methyl O CH CF CH CH CH CH CH NHCH₃ CH₂ CH₃ imidazolyl2-N-Methyl O N CF CH CH CH CH CH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl OCH CF CH CH CH CCH₃ CH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O CH CF CH CHCH CI CH NHCH₃ CH₂ CH₃ imidazolyl[where the combinations of G⁹, Z¹³, Z¹⁴, Z¹⁵, G¹, G², G³, NR⁶R⁷, G⁷ andR² are as listed in the table below.]

X G⁹ Z¹³ Z¹⁴ Z¹⁵ G¹ G² G³ NR⁶R⁷ G⁷ R² (CH₃)₂NCO O S CH CH CH CH CH NHCH₃CH₂ CH₃ (CH₃)₂NCO O CH S CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH SCH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O NH CH CH CH CH CH NHCH₃ CH₂ CH₃(CH₃)₂NCO O CH NH CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH NH CH CHCH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O O CH CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO OCH O CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH O CH CH CH NHCH₃ CH₂CH₃ (CH₃)₂NCO O S NH CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O N CH NH CH CHCH NHCH₃ CH₂ CH₃ (CH₃)₂NCO S S CH CH CH CH CH NHCH₃ CH₂ CH₃ (CH₃)₂NCOCH₂ S CH CH CH N CH NHCH₃ S CH₃ (CH₃)₂NCO CF₂ CH S CH CH N CH NHCH₃ SOCH₃ 2-Pyrimidinyl O S CH CH CH CH CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH SCH CH CH CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CH S CH CH CH NHCH₃ CH₂ CH₃2-Pyrimidinyl O S CH CH CH N CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH S CH CHCCH₃ CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CH S N CH CH NHCH₃ CH₂ CH₃2-Pyrimidinyl O S CH CH CH CH CH NHCH₃ O CH₃ 2-Pyrimidinyl O CH S CH CHCH CH NHCH₃ S CH₃ 2-Pyrimidinyl O CH CH S CH CH CH NHCH₃ NH CH₃2-Thiazolyl O S CH CH CH CH CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O CH S CH CH CHCH NHCH₃ CH₂ CH₃ 2-Thiazolyl O CH CH S CH CH CH NHCH₃ CH₂ CH₃ 2-N-MethylO S CH CH CH CH CH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O CH CH S CH CCH₃CH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O N S CH CH CCH₃ CH NHCH₃ S CH₃imidazolyl

Examples of manufacturing processes for the compound or salt accordingto the present invention will now be explained. In each of themanufacturing processes explained hereafter, the order of steps may bechanged as may be necessary. Furthermore, when a reactant in a certainstep is subjected to an undesired chemical conversion under reactionconditions for the step, the manufacturing process may be carried outby, for example, performing protection and deprotection of a functionalgroup. For selection of a protecting group and a method of protectionand deprotection, there may be referred to, for example, T. W. Greene,P. G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition,John Wiley and Sons, Inc., New York, 1991.

X, Y¹, Y², Y³, Y⁴, R¹, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the same meaningsas mentioned above, while Hal represents a halogen atom; R^(a)represents a C₁₋₆ alkyl group (the C₁₋₆ alky group may be substitutedwith a substituent selected from the group consisting of a fluorineatom, an optionally protected hydroxy group, an optionally protected oxogroup, and an optionally protected carboxy group); R^(b) represents aleaving group, such as a halogen atom or 2-oxazolidinon-3-yl group;R^(c) represents a protecting group for the carboxy group, such as aC₁₋₄ alkyl group; R^(d) and R^(e) are the same or different, and eachindependently or together represent a protecting group for the aminogroup; R^(f) represents a C₁₋₄ alkyl group; R^(g) represents a hydroxygroup or halogen atom; R^(h) represents a methyl group or R^(c)OCO—;R^(i) represents a hydrogen atom or C₁₋₅ alkyl group; and B represents anitro group or —NR^(d)R^(e).

(General Process-1)

General process-1 is an example of a particularly preferredmanufacturing process for a compound of general formula (1) wherein R²is R^(a), and Y¹ and Y² are the same or different, and are each —CR¹¹═.

Step 1-1:

Compound 1c can be obtained by condensation between a deprotonated formof compound 1b, which is obtained by reaction of compound 1b with abase, and compound 1a.

As for the base, there may be mentioned, for example, sodium hydride,potassium hydride, lithium hexamethyldisilazide (also referred to as“LiHMDS” herein) and the like, among which sodium hydride and the likeare preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas tetrahydrofuran (also referred to as “THF” herein) and diethylether;and chlorine solvents such as methylene chloride, among which THF ispreferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while for the reactionbetween compound 1b and a base, it is generally −20° C. to 25° C.,preferably 0° C. to 10° C., and for the condensation between thedeprotonated form and compound 1a, it is generally 0° C. to 60° C.,preferably 15° C. to 35° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while for the reaction betweencompound 1b and a base, it is generally 10 minutes to 3 hours,preferably 20 minutes to 1 hour, and for the condensation between thedeprotonated form and compound 1a, it is generally 2 hours to 20 hours,preferably 5 hours to 15 hours.

As for the method for subjecting the deprotonated form and compound 1ato the reaction, it is preferred to add dropwise a solution containingthe deprotonated form to a solution containing compound 1a.

Step 1-2:

Compound 1e can be obtained by reaction between compound 1c and compound1d in the presence of acid.

As for the acid, there may be mentioned: Lewis acids such as zirconiumchloride, samarium(II) chloride and aluminum chloride; inorganic acidssuch as sulfuric acid; and acidic resins such as zeolite, among whichsulfuric acid is preferred.

As for the reaction solvent, solvents inactive for the reaction may beused, while solvent-free conditions are preferred. When sulfuric acid isused, the number of equivalents is generally 1 to 5, preferably 1 to 3,relative to compound 1d.

The reaction temperature is generally −20° C. to 50° C., preferably −10°C. to 30° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 2 hours to 20hours, preferably 5 hours to 16 hours.

Step 1-3:

Compound 1g can be obtained by reaction between compound 1e and compound1f in the presence of base.

As for the base, there may be mentioned, for example: weakly basicinorganic salts such as sodium carbonate, potassium carbonate and cesiumcarbonate; and metal hydrides such as sodium hydride and potassiumhydride, among which potassium carbonate, cesium carbonate and sodiumhydride are preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas tetrahydrofuran and diethylether; and N,N-dimethylformamide and thelike, among which tetrahydrofuran and N,N-dimethylformamide arepreferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while for cases where X is anelectron-deficient heteroaryl group such as a pyridyl or pyrimidinylgroup, it is generally 60° C. to 150° C., preferably 70° C. to 100° C.;for cases where X is an electron-rich heteroaryl group such as athiazolyl group, it is generally 90° C. to 200° C., preferably 100° C.to 120° C.; and for cases where X is a group represented by R³R⁴NCO—, itis generally 0° C. to 50° C., preferably 0° C. to 30° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 30 minutes to 5hours, preferably 40 minutes to 2 hours.

Furthermore, when X is an electron-rich heteroaryl group such as athiazolyl group, it is preferred to perform the reaction whileirradiating microwave in the coexistence of a monovalent copper saltsuch as copper(I) iodide, CuPF₆ or Cu(I)OTf (copper(I)trifluoromethanesulfonate), preferably copper(I) iodide or the like.

Step 1-4:

Compound 1h can be obtained by reduction of compound 1g.

As for the reducing agent, there may be mentioned tin(II) chloride, zincand the like, among which tin(II) chloride is preferred.

As for the reaction solvent, there may be mentioned: alcohol solventssuch as methanol and ethanol; acetic acid ester solvents such as ethylacetate, n-propyl acetate and n-butyl acetate; and mixtures thereof,among which ethyl acetate, and a mixture of ethanol and ethyl acetateare preferred.

The reaction temperature is generally 50° C. to 150° C., preferably 60°C. to 90° C.

The reaction time is generally 30 minutes to 5 hours, preferably 1 hourto 3 hours.

Compound 1h can also be obtained by subjecting compound 1a to step 1-4,step 1-1, step 1-2 and step 1-3 in this order, or by subjecting compound1c to step 1-4, step 1-2 and step 1-3 in this order.

Furthermore, compound 1h can also be obtained from a compound other thancompound 1g by catalytic hydrogenation using palladium carbon or thelike as the catalyst, referring to Bioorganic and Medicinal ChemistryLetters, 2004, 14, 2411-2415.

Step 1-5:

Compound 1j can be obtained by reaction between compound 1h and compound1i.

As for the reaction solvent, there may be mentioned methylene chloride,acetonitrile, N,N-dimethylformamide and the like, among which, from theviewpoint of solubility of compound 1h, acetonitrile,N,N-dimethylformamide and the like are preferred.

The reaction temperature is generally 15° C. to 120° C., preferably 20°C. to 85° C.

The reaction time is generally 1 hour to 2 days, preferably 2 hours to24 hours.

Furthermore, it is preferred to perform the reaction in the coexistenceof base. As for the base, organic amines such as pyridine, triethylamineand diisopropylethylamine are preferred.

Step 1-6:

Compound 1m can be obtained by subjecting compound 1h to reaction withcompound 1l in the presence of base, and then converting Rc to ahydrogen atom by deprotection.

In the reaction with compound 1l, as for the base, there may bementioned organic amines such as pyridine, triethylamine anddiisopropylethylamine, among which diisopropylethylamine and the likeare preferred.

As for the reaction solvent, there may be mentioned ether solvents suchas diethylether, THF and dioxane, among which THE is preferred.

The reaction temperature is generally 10° C. to 50° C., preferably 15°C. to 40° C.

The reaction time is generally 20 minutes to 2 hours, preferably 30minutes to 1 hour.

As for the method for the deprotection, hydrolysis in the presence ofbase is preferred.

As for the base, there may be mentioned metal hydroxides such as sodiumhydroxide and potassium hydroxide, among which sodium hydroxide and thelike are preferred.

As for the reaction solvent, there may be mentioned: alcohol solventssuch as methanol, ethanol and n-propanol; water; and mixtures thereof,among which a mixture of water and methanol is preferred.

The reaction temperature and reaction time are the same as those forcompound 1l.

Step 1-8:

Compound 1o can be obtained by condensation between compound 1m andcompound 1n.

As for the condensing agent, there may be mentioneddicyclohexylcarbodiimide, carbonyldiimidazole,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the like, among which1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and the like arepreferred. Furthermore, it is preferred to perform the condensation inthe coexistence of an active esterifying agent such asN-hydroxysuccinimide, N-hydroxybenzotriazole or3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole (preferably3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole or the like).

As for the reaction solvent, there may be mentioned: ether solvents suchas diethylether, THF and dimethoxyethane; halogen solvents such asmethylene chloride, chloroform and carbon tetrachloride; andN,N-dimethylformamide, acetonitrile and the like, among whichN,N-dimethyl formamide is preferred.

The reaction temperature is generally 10° C. to 50° C., preferably 15°C. to 40° C.

The reaction time is generally 5 hours to 40 hours, preferably 10 hoursto 25 hours.

Step 1-7 and Step 1-9:

Compound 1k and compound 1p can be obtained by introducing a C₁₋₆ alkylgroup into compound 1j and compound lo as necessary.

The introduction of C₁₋₆ alkyl can be performed referring to, forexample, methods described in Bioorganic and Medicinal Chemistry 2005,13, 1393-1402, Organic Preparations and Procedures International 2004,36, 347-351, and Journal of Medicinal Chemistry 2004, 47, 6447-6450.

Compound 1k can also be obtained by subjecting compound 1h to step 1-7and step 1-5 in this order. Compound 1p can also be obtained bysubjecting compound 1h to step 1-9, step 1-6 and step 1-8 in this order.

Compound 1b is commercially available, and can be produced referring to,for example, methods described in common textbooks of organic chemistry(for example, Jerry March, WILEY INTERSCIENCE Advanced Organic Chemistry4th edition). Compound 1d is commercially available, and can be producedreferring to methods described in, for example, Journal of FluorineChemistry 2003, 120, 173-183, and Journal of Organic Chemistry 1986, 51,3242-3244.

(General Process-2)

General process-2 is an example of a manufacturing process for compound1a of general process-1.

Step 2-1:

Compound 1a can be obtained by halogenation, preferably bromination, ofcompound 2a.

As for the halogenating agent, there may be mentionedN-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide and the like,among which N-bromosuccinimide is preferred.

As for the reaction solvent, inactive nonpolar solvents such as carbontetrachloride are preferred.

The reaction temperature is generally 20° C. to 100° C., preferably 50°C. to 90° C.

The reaction time is generally 30 minutes to 10 hours, preferably 1 hourto 7 hours.

Step 2-2:

Compound 2c can be obtained by reduction of compound 2b.

As for the reducing agent, there may be mentioned lithium aluminumhydride, diisobutylaluminum hydride (also referred to as “DIBAH” herein)and the like, among which DIBAH is preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas diethylether, and THF; and benzene solvents such as benzene, tolueneand xylene, among which, when DIBAH is used as the reducing agent,toluene and the like are preferred.

The reaction temperature is generally −100° C. to 10° C., preferably−85° C. to 0° C.

The reaction time is generally 10 minutes to 3 hours, preferably 30minutes to 2 hours.

Compound 2c can also be obtained by converting the R^(c)OCO— of compound2b to a formyl group and subjecting the obtained compound to step 2-2.

Step 2-3:

Compound 1a can be obtained by converting the hydroxy group of compound2c to a halogen atom, preferably a bromine atom.

As for the halogenating agent, there may be mentioneddiethylaminosulfurtrifluoride (also referred to as “DAST” herein),thionyl chloride, phosphorus tribromide, a combination oftriphenylphosphine and iodine, and a combination of paratoluenesulfonicacid chloride and sodium iodide, among which phosphorus tribromide ispreferred.

As for the reaction solvent, there may be mentioned ether solvents suchas diethylether, THF and dioxane, among which diethylether is preferred.

The reaction temperature is generally −10° C. to 10° C., preferably −5°C. to 5° C.

The reaction time is generally 10 minutes to 1 hour, preferably 20minutes to 40 minutes.

Compound 2a and compound 2b are commercially available, and can beproduced referring to, for example, methods described in commontextbooks of organic chemistry (for example, Jerry March, WILEYINTERSCIENCE Advanced Organic Chemistry 4th edition). Compound 2b canalso be produced by, for example, performing any one of the following(i) to (iii), regarding the corresponding halogenated aryl compound(i.e., a compound obtained by replacing the —COOR^(c) of compound 2b bya halogen atom): (i) converting the halogen atom to a carboxy group;(ii) subjecting the halogenated compound to reaction with copper(I)cyanide in sulfuric acid (Journal of Antibiotics 1994, 47, 1456-1465;Liebigs Annalen Chemie 1979, 4, 554-563); and (iii) inserting carbonmonoxide at the position at which the halogen atom is bound, usingpalladium catalyst (Journal of Organic Chemistry 1999, 64, 6921-6923).

(General Process-3)

General process-3 is an example of a particularly preferredmanufacturing process for a compound 2a or 2b of general process-2wherein Y² is —CF═.

Step 3-1:

Compound 3b can be obtained by subjecting compound 3a (wherein Hal ispreferably a chlorine atom) to reaction with a fluorinating agent suchas sodium fluoride, potassium fluoride and cesium fluoride (preferablycesium fluoride). A quaternary ammonium salt such as tetramethylammoniumchloride may be added as necessary.

As for the reaction solvent, dimethylsulfoxide, sulforane andN,N-dimethylformamide and the like are preferred.

The reaction temperature is generally 100° C. to 200° C., preferably120° C. to 160° C.

In cases where R^(h) is a methyl group, the reaction time is generally 5hours to 20 hours, preferably 7 hours to 15 hours; and in cases whereR^(h) is R^(c)OCO—, the reaction time is generally 20 minutes to 2hours, preferably 30 minutes to 1 hour.

Compound 3b, particularly a compound wherein Y¹, Y³ and Y⁴ are each—CH═, is a novel compound, and is useful as a synthetic intermediate toa compound represented by general formula (1).

Compound 3a is commercially available, and can be produced referring to,for example, methods described in Yakugaku Zasshi 1955, 75, 292-296 andcommon textbooks of organic chemistry (for example, Jerry March, WILEYINTERSCIENCE Advanced Organic Chemistry 4th edition).

(General Process-4)

General process-4 is another manufacturing process for compound 1h.

Step 4-1:

Compound 4a can be synthesized by reduction of compound 1e. This stepcan be carried out in the same way as step 1-4.

Step 4-2:

Compound 1h can be obtained by reaction between compound 4a and compound1f in the presence of base. This step can be carried out in the same wayas step 1-3.

(General Process-5)

General process-5 is still another manufacturing process for compound1h. With this process, a compound 1h wherein Y¹ and Y² are eachindependently —N═ or —CR¹¹═ can be produced.

Step 5-1:

Compound 5b can be obtained by protecting the amino group of compound5a, preferably by converting R^(d) and R^(e) to a t-butoxycarbonylgroup.

As for the protecting agent, Boc₂O (di-t-butylcarbonate) and the likeare preferred.

As for the reaction solvent, there may be mentioned ether solvents suchas diethylether and THF, among which THF and the like are preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 0° C.to 90° C., preferably 20° C. to 70° C.

The reaction time is generally 2 hours to 2 days, preferably 3 hours to20 hours.

Furthermore, it is preferred to perform the reaction in the coexistenceof a reaction accelerator such as N,N-dimethylaminopyridine.

Step 5-2:

Compound 5c can be obtained by halogenation, preferably bromination, ofcompound 5b.

As for the halogenating agent, there may be mentioned chlorine molecule,bromine molecule, iodine molecule, N-chlorosuccinimide,N-bromosuccinimide, N-iodosuccinimide and the like, among whichN-bromosuccinimide is preferred. Furthermore, it is preferred to performthe halogenation in the coexistence of a radical initiator such asazoisobutylonitrile or benzoyl peroxide (preferably benzoyl peroxide orthe like).

As for the reaction solvent, there may be mentioned halogen solventssuch as carbon tetrachloride and chloroform; nonpolar hydrocarbonsolvents such as cyclohexane and hexane, among which carbontetrachloride is preferred.

The reaction temperature is generally 50° C. to 100° C., preferably 70°C. to 90° C.

The reaction time is generally 1 hour to 8 hours, preferably 2 hours to6 hours.

Step 5-3:

Compound 5t can be obtained by subjecting compound 5c to reaction withcompound 1b in the presence of base.

As for the base, there may be mentioned, for example, metal hydridessuch as sodium hydride, potassium hydride and LiHMDS, among which sodiumhydride and the like are preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas THF and diethylether; and chlorine solvents such as methylenechloride, among which THE is preferred.

The reaction temperature is generally −20° C. to 25° C., preferably 0°C. to 10° C.

The reaction time is generally 2 hours to 24 hours, preferably 6 hoursto 15 hours.

Furthermore, compound 5t can be obtained by the condensation reactiondescribed in International Publication WO 2002/08217 followed bycatalytic hydrogenation.

Step 5-4:

Compound 5d can be obtained by performing deprotection of the aminogroup at the same time as condensation reaction of compound 5t andcompound 1d in the presence of acid.

As for the acid, there may be mentioned: Lewis acids such as zirconiumchloride, samarium(H) chloride and aluminum chloride; inorganic acidssuch as sulfuric acid; and acidic resins such as zeolite, among whichsulfuric acid is preferred.

As for the reaction solvent, solvents inactive for the reaction may beused, while solvent-free conditions are preferred. When sulfuric acid isused, the number of equivalents is generally 1 to 5, preferably 1 to 3,relative to compound 1d.

The reaction temperature is generally −20° C. to 50° C., preferably −10°C. to 30° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 2 hours to 20hours, preferably 5 hours to 16 hours.

Step 5-5:

Compound 1h can be obtained by subjecting compound 5d to reaction withcompound 1f in the presence of base. This step can be carried out in thesame way as step 1-3.

Compound 5a is commercially available, and can be produced referring to,for example, methods described in European Journal of MedicinalChemistry 1999, 34, 1003-1008, Bioorganic and Medicinal ChemistryLetters 2004, 16, 1411-1416, Bioorganic and Medicinal Chemistry Letters2002, 12, 2109-2112, Chemical and Pharmaceutical Bulletin 2004, 52,818-829, and the like. Furthermore, compound 5a and compound 5b can alsobe produced by, for example, introducing a nitrogen atom into thecorresponding halogenated aryl compound (i.e., a compound obtained byreplacing the amino group or —NR^(d)R^(e) of compound 5a or 5b by ahalogen atom) at the position at which the halogen atom is bound, usingpalladium catalyst (Organic Letters 2002, 4, 4689-4692).

In general processes-1, -4, -5 and -8, from a compound wherein R^(a) isa C₁₋₆ alkyl group (the C₁₋₆ alkyl group is substituted with asubstituent selected from the group consisting of an optionallyprotected hydroxy group, an optionally protected oxo group, and anoptionally protected carboxy group), it is possible to produce acompound of general formula (1) wherein R² is a C₁₋₆ alkyl groupsubstituted with a halogen atom, by converting the optionally protectedhydroxy group, the optionally protected oxo group or the optionallyprotected carboxy group to a halogen atom. Conversion to a fluorine atomcan be performed at an appropriate step of general processes-1, -4, -5and -8 using DAST or the like as a fluorinating agent, referring toSynthesis 2002, 17, 2561-2578 or the like. Conversion to a chlorine atomor bromine atom can be performed using compound 1j, compound 1o or thelike and using thionyl chloride, PBr₃ or the like as a halogenatingagent, referring to Larock, Comprehensive Organic Transformations or thelike.

(General Process-6)

General process-6 is an example of a preferred manufacturing process fora compound of general formula (1) wherein R² is a C₁₋₆ alkyl groupsubstituted with a fluorine atom.

Step 6-1:

Compound 6b can be obtained by introducing a halogen atom, preferably abromine atom, into compound 6a.

As for the halogenating agent, there may be mentioned, for example,N-chloro succinimide, N-bromosuccinimide, N-iodosuccinimide and thelike, among which N-bromosuccinimide is preferred.

As for the reaction solvent, there may be mentioned carbontetrachloride, diethylether, THF and the like, among which THF and thelike are preferred.

The reaction temperature is generally −50° C. to 10° C., preferably −20°C. to 5° C.

The reaction time is generally 20 minutes to 2 hours, preferably 30minutes to 1 hour.

Step 6-2:

Compound 6c can be obtained by further replacing the halogen atom ofcompound 6b by a fluorine atom.

As for the fluorinating agent, there may be mentioned fluorinated metalssuch as potassium fluoride and sodium fluoride, among which potassiumfluoride is preferred. It is preferred to perform the fluorination inthe coexistence of a crown ether (for example, 18-crown-6) correspondingto a metal in the fluorinated metal to be used.

As for the reaction solvent, acetonitrile, for example, is preferred.

The reaction temperature is generally 20° C. to 100° C., preferably 20°C. to 80° C.

The reaction time is generally 1 hour to 6 hours, preferably 1.5 hoursto 5 hours.

It is possible to produce a compound of general formula (1) wherein R₂is a C₁₋₆ alkyl group substituted with a fluorine atom, by deprotectingcompound 6c as necessary, and then subjecting it to step 1-4, step 1-5or step 1-6, and the subsequent steps of general process-1.

(General Process-7)

General process-7 is an example of a preferred manufacturing process fora compound of general formula (1) wherein R² is a C₁₋₆ alkyl groupsubstituted with a halogen atom.

Step 7-1:

Compound 7c can be obtained by subjecting a deprotonated form ofcompound 1g, which is obtained by reaction between compound 1g and abase, to reaction with compound 7b.

As for the base, there may be mentioned sodium hydride, potassiumhydride, LiHMDS and the like, among which LiHMDS is preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas THF and diethylether; and chlorine solvents such as methylenechloride, among which THF is preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while for the reactionbetween compound 1g and a base, it is generally −100° C. to 10° C.,preferably −85° C. to 5° C., and for the reaction between thedeprotonated form and compound 7b, it is generally −5° C. to 40° C.,preferably 0° C. to 30° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while for the reaction betweencompound 1g and a base, it is generally 20 minutes to 3 hours,preferably 30 minutes to 1.5 hours, and for the reaction between thedeprotonated form and compound 7b, it is generally 20 minutes to 20hours, preferably 30 minutes to 15 hours.

Step 7-3:

Compound 7f can be obtained by subjecting a deprotonated form ofcompound 1g, which is obtained by reaction between compound 1 g and abase, to reaction with compound 7e. This step can be carried out in thesame way as step 7-1.

Step 7-2 and Step 7-4:

Compound 7d and compound 7g can be obtained by reduction of compound 7cand compound 7f, respectively. This step can be carried out in the sameway as step 1-4.

It is possible to produce a compound of general formula (1) wherein R²is a C₁₋₆ alkyl group substituted with a halogen atom, by convertingcompound 7d or compound 7g by the same method as in general process-1.

A compound wherein R² is a C₁₋₆ alkyl group substituted with a fluorineatom can also be produced by converting the introduced hydroxy or oxogroup of compound 7c or 7f to a fluorine atom, and then subjecting it tostep 1-4 and the subsequent steps of general process-1. The conversionof the hydroxy or oxo group to a fluorine atom can be performed usingDAST or the like as a fluorinating agent, referring to Synthesis 2002,17, 2561-2578 or the like.

(General Process-8)

General process-8 is another manufacturing process for compound 5t, andis an example of a particularly preferred manufacturing process for acompound of general formula (1) wherein Y¹ is —N═.

[where R^(j) represents a leaving group, such as a halogen atom, C₁₋₄alkoxy group or di(C₁₋₄ alkyl)amino group, or a hydrogen atom; and R^(k)represents a leaving group, such as an acetyloxy group,trifluoroacetyloxy group, methanesulfonyloxy group,paratoluenesulfonyloxy group or halogen atom.]

Step 8-1:

Compound 8b can be obtained by subjecting a deprotonated form ofcompound 8a, which is obtained by reaction between compound 8a and astrong base, to reaction with a compound represented by formula:R^(j)CHO (hereinafter also referred to simply as “R^(j)CHO”).

As for the strong base, there may be mentioned: metal amides such aslithium hexamethyldisilazide and lithium diisopropylamide; alkylmetalssuch as butyllithium and ethyllithium; and alkylmagnesium halide and thelike, among which lithium hexamethyldisilazide, lithium diisopropylamideand the like are preferred. As for R^(j)CHO, there may be mentioned:formic acid derivatives such as formyl chloride and formic acid esters;formamides such as N,N-dimethylformamide (also referred to as “DMF”herein) and N,N-diethylformamide, among which DMF is preferred. By usingformaldehyde as R^(j)CHO, it is possible to obtain compound 8c directlyfrom compound 8a without producing compound 8b.

As for the reaction solvent, there may be mentioned: ether solvents suchas TIM and diethylether; and chlorine solvents such as methylenechloride and carbon tetrachloride, among which THF is preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while for the reactionbetween compound 8a and a strong base, it is generally −100° C. to 25°C., preferably −95° C. to −65° C., and for the reaction between thedeprotonated form and R^(j)CHO, it is generally −100° C. to 35° C.,preferably −30° C. to 10° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while for the reaction betweencompound 8a and a strong base, it is generally 10 minutes to 10 hours,preferably 20 minutes to 5 hours, and for the reaction between thedeprotonated form and R^(j)CHO, it is generally 30 minutes to 40 hours,preferably 30 minutes to 4 hours.

Step 8-2:

Compound 8c can be obtained by reaction between compound 8b and areducing agent.

As for the reducing agent, there may be mentioned metal-hydrogen complexcompounds (for example, metal borohydrides, such as sodium borohydride,sulfurated sodium borohydride, sodium cyanoborohydride, sodiumtrimethoxyborohydride, lithium borohydride, lithium cyanoborohydride,lithium triethylborohydride, lithium tri-s-butylborohydride, lithiumtri-t-butylborohydride, calcium borohydride, potassium borohydride,potassium triisopropoxyborohydride, potassium tri-s-butylborohydride,zinc borohydride, and sodium triacetoxyborohydride; and metal aluminumhydrides, such as lithium aluminum hydride, lithium trimethoxyaluminumhydride, lithium tri-t-butoxyaluminum hydride, lithium aluminumhydride/trichloroaluminum, lithium aluminum hydride/boron trifluoride,chloromagnesium aluminum hydride, magnesium aluminum hydride, sodiumaluminum hydride, sodium triethoxyaluminum hydride, and sodiumbis(methoxyethoxy)aluminum hydride), among which metal borohydrides suchas sodium borohydride are preferred.

As for the reaction solvent, there may be mentioned: ether solvents suchas THF and diethyl ether; chlorine solvents such as methylene chlorideand carbon tetrachloride; and alcohol solvents such as methanol andethanol, among which THF is preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally −100°C. to 100° C., preferably −10° C. to 50° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 10 minutes to30 hours, preferably 1 hour to 8 hours.

Step 8-3:

Compound 8d can be obtained by reaction between compound 8c and anaminating agent.

As for the aminating agent, there may be mentioned: ammonia; aqueousammonia; ammonium salts such as ammonium chloride and ammonium acetate;metal amides such as lithium hexamethyldisilazide, potassiumhexamethyldisilazide, sodium hexamethyldisilazide, lithium amides,sodium amides and potassium amides; and silazanes such ashexamethyldisilazane, among which ammonia, and metal amides such aslithium hexamethyldisilazide are preferred.

When ammonia is used as the aminating agent, the reaction can beperformed in the coexistence of an organic amine such as triethylamine,a base such as sodium hydroxide, or the like. When a metal amide such aslithium hexamethyldisilazide is used as the aminating agent, thereaction can be performed in the coexistence of palladium catalyst andphosphine ligand which can be used in step 8-5.

As for the reaction solvent, there may be mentioned: hydrocarbonsolvents such as toluene and benzene; ether solvents such as THF,diethylether and dioxane; chlorine solvents such as methylene chloride;and non-proton polar solvents such as DMF, among which toluene, DMF anddioxane are particularly preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 0° C.to 200° C., preferably 30° C. to 150° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 1 hour to 30hours, preferably 2 hours to 10 hours.

Compound 8d can also be obtained by protecting the hydroxy group ofcompound 8c, then subjecting the compound to this step, and thendeprotecting the hydroxy group.

For selection of a protecting group and a method of protection anddeprotection, there may be referred to, for example, T. W. Greene, P. G.M. Wuts, Protective Groups in Organic Synthesis, Second Edition, JohnWiley and Sons, Inc., New York, 1991. As preferred examples of theprotecting group, there may be mentioned: trisubstituted silyl groups,such as a trimethylsilyl group, triethylsilyl group, triisopropylsilylgroup, dimethylisopropylsilyl group, diethylisopropylsilyl group,dimethylthexylsilyl group, tert-butyldimethylsilyl group,tert-butyldiphenylsilyl group, tribenzylsilyi group, tri-p-xylylsilylgroup, triphenylsilyl group, diphenylmethylsilyl group andtert-butylmethoxyphenylsilyl group; and substituted benzyl groups, suchas a benzyl group, triphenylmethyl group, 2,4,6-trimethylbenzyl group,p-bromobenzyl group, o-nitrobenzyl group, p-nitrobenzyl group,p-methoxybenzyl group and 2,6-dimethoxybenzyl group, among which atert-butyldimethylsilyl group (also referred to as “TBS group” herein)is preferred.

When the protecting group is a trisubstituted silyl group, theprotection of the hydroxy group can be performed by subjecting compound8c to reaction with a trisubstituted silyl halide in the presence ofbase.

As for the base, there may be mentioned amities such as triethylamine,pyridine, imidazole, triazole, benzimidazole and benzotriazole, amongwhich imidazole is preferred.

As for the halide, there may be mentioned a chloride, bromide andiodide, among which a chloride is preferred.

As for the reaction solvent, there may be mentioned amide solvents suchas N,N-dimethylacetamide, N,N-dimethylimidazoliclinone (also referred toas “DMI” herein) and DMF, among which DMF is preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 0° C.to 150° C., preferably 15° C. to 65° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 30 minutes to30 hours, preferably 1 hour to 5 hours.

When the protecting group is a trisubstituted silyl group, thedeprotection of the protected hydroxy group of compound 8d can beperformed by, for example, subjecting the compound to reaction with anacid and a fluoride reagent.

As for the acid, there may be mentioned: inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and perchloric acid; and organic acids such astrifluoroacetic acid, trichloroacetic acid, methanesulfonic acid,p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid,oxalic acid and citric acid; and acidic ion-exchange resins may furtherbe mentioned.

As for the fluoride reagent, there may be mentionedtetra-n-butylammonium fluoride, hydrogen fluoride/pyridine, hydrogenfluoride/triethylamine, hydrofluoric acid, lithium fluoride, sodiumfluoride, potassium fluoride, cesium fluoride and the like, among whichtetra-n-butylammonium fluoride and the like are preferred.

The reaction solvent may be appropriately determined, and there may beused, for example: alcohol solvents; ether solvents such as THF anddiethylether; ester solvents such as ethyl acetate and methyl acetate;nitrile solvents such as acetonitrile, benzonitrile and benzyl cyanide;and amide solvents such as N,N-dimethylacetamide, DMI and DMF, amongwhich ether solvents such as THF are preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 0° C.to 150° C., preferably 15° C. to 65° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 5 minutes to 30hours, preferably 10 minutes to 3 hours.

Step 8-4:

Compound 8e can be obtained by protecting the amino group of compound8d.

As for the method for protection of the amino group, methods usingvarious protecting groups generally usable in organic chemistry arementioned, while preferred are, for example, a method of forming acarbamate using a t-butoxycarbonyl group or the like, a method offorming an imine using a phenylmethylidenyl group, diphenylmethylidenylgroup or the like, and a method of forming an amide by acetylation,trifluoroacetylation or the like, and particularly preferred are amethod of forming a carbamate using a t-butoxycarbonyl group or thelike, and a method of forming an imine using a diphenylmethylidenylgroup or the like.

The method of forming a carbamate may be carried out in the same way asstep 5-1.

The method of forming an imine may be carried out by heating compound 8dtogether with an aldehyde such as benzaldehyde, or a ketone such asbenzophenone.

As for the reaction solvent, alcohol solvents such as methanol, ethanol,n-propanol and i-propanol are preferred, and methanol is particularlypreferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 10° C.to 120° C., preferably 40° C. to 90° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 30 minutes to20 hours, preferably 1 hour to 5 hours.

Step 8-5:

Compound 8e can also be obtained by subjecting compound 8c to reactionwith a compound represented by formula: HNR^(d)R^(e) (hereinafter alsoreferred to simply as “HNR^(d)R^(e)”).

As for HNR^(d)R^(e), there may be mentioned, for example: acetamidessuch as acetamide and bis(trimethylsilyl)acetamide; imines such asdiphenylimine; and aralkylamines such as benzylamine, among whichacetamide, bis(trimethylsilyl)acetamide and diphenylimine are preferred.

It is preferred to perform the reaction in the coexistence of palladiumcatalyst and phosphine ligand to accelerate it.

As for the palladium catalyst, there may be mentioned palladium acetate,palladium trifluoroacetate, palladium chloride, palladium carbon,allylpalladium chloride dimer, tetrakis(triphenylphosphine)palladium,bis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium,tris(dibenzylideneacetone)dipalladium-chloroform adduct,dichlorobis(triphenylphosphine)palladium,bis(acetonitrile)dichloropalladium and the like, among whichbis(dibenzylideneacetone)palladium,tris(dibenzylideneacetone)dipalladium and the like are preferred.

As for the phosphine ligand, there may be mentioned triphenylphosphine,tri-o-tolylphosphine, tri(2-furyl)phosphine, tri-t-butylphosphine,tricyclohexylphosphine, tri-n-butylphosphine,1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane,1,4-bis(diphenylphosphino)butane, 1,1′-bis(diphenylphosphino)ferrocene,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,dicyclohexyl[2′,4′,6′-tris(1-methylethyl)-1,1′-biphenyl-2-yl]phosphine(X-Phos) and the like, among which2,2′-bis(diphenylphosphino)-1,1′-binaphthyl anddicyclohexyl[2′,4′,6′-tris(1-methylethyl)-1,1′-biphenyl-2-yl]phosphine(X-Phos) are preferred.

As for the reaction solvent, there may be mentioned: hydrocarbonsolvents such as hexane, heptane, octane, toluene, benzene and xylene;ether solvents such as THE, diethylether and dioxane; and non-protonpolar solvents such as DMF and N,N-dimethylacetamide, among whicharomatic hydrocarbon solvents such as toluene and benzene are preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally 20° C.to 140° C., preferably 45° C. to 80° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 1 hour to 30hours, preferably 5 hours to 20 hours.

Compound 8e can also be obtained by protecting the hydroxy group ofcompound 8c, then subjecting the compound to this step, and thendeprotecting the hydroxy group. This may be carried out in the same wayas the process of protecting the hydroxy group of compound 8c, thensubjecting the compound to step 8-3, and then deprotecting the hydroxygroup to yield compound 8d.

Step 8-6:

Compound 8f can be obtained by converting the hydroxy group of compound8e to a leaving group, for example, by esterification (acetylation,mesylation, tosylation or the like) of the hydroxy group, or replacementof the hydroxy group by a halogen atom, preferably by sulfonateesterification (mesylation, tosylation or the like) of the hydroxygroup.

The sulfonate esterification of compound 8e can be performed bysubjecting compound 8e to reaction with methanesulfonyl chloride,para-toluenesulfonyl chloride or the like in the presence of base.

As for the base, there may be mentioned, for example: metal hydridessuch as sodium hydride, potassium hydride and lithium hydride; and metalalkoxides such as potassium t-butoxide, sodium t-butoxide, lithiumt-butoxide, potassium t-pentoxide, sodium t-pentoxide and lithiumt-pentoxide, among which metal alkoxides such as lithium t-butoxide arepreferred.

As for the reaction solvent, ether solvents such as THF, diethyletherand dioxane are preferred, and THF is particularly preferred.

The reaction temperature may be appropriately determined depending onthe type of reaction solvent and the like, while it is generally −90° C.to 30° C., preferably −50° C. to 10° C.

The reaction time may be appropriately determined depending on thereaction temperature and the like, while it is generally 5 minutes to 10hours, preferably 15 minutes to 2 hours.

The acetate esterification (acetylation, trifluoroacetylation or thelike) of compound 8e can be easily performed by a method generally usedin organic chemistry. For example, it can be performed by subjectingcompound 8e to reaction with the corresponding acid halide (acetylchloride, trifluoroacetyl chloride or the like) or acid anhydride(acetic anhydride, trifluoroacetic anhydride or the like) in thepresence of base.

The halogenation of compound 8e can be performed in the same way as step2-3. Furthermore, it can also be carried out by performing an exchangereaction between the sulfonate ester obtained by the above-mentionedsulfonate esterification, and a halogen anion.

Step 8-7:

Compound 5t can be obtained by subjecting compound 8f to reaction withcompound 1b in the presence of base. This step can be carried out in thesame way as step 5-3.

Compound 8a is commercially available, and can be produced referring to,for example, methods described in common textbooks of organic chemistry(for example, Jerry March, WILEY INTERSCIENCE Advanced Organic Chemistry4th edition). As for Hal in compound 8a, a chlorine atom is preferred.Some examples of compounds 8b and 8c are known compounds which arereadily available.

Based on general processes-1 to -8, and examples which will be describedlater, or referring thereto, the following compounds, for example, canalso be synthesized:

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-(aminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-1-benzopyran,

3-{2-chloro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-methyl-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,

3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran,and

3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(N-methylimidazol-2-yloxy)-2-oxo-2H-1-benzopyran.

The present invention includes pharmaceutically acceptable salts ofcompounds represented by general formula (11), preferably generalformula (1). These salts are produced by contacting the compound with anacid or base usable for production of pharmaceutical products. Examplesof the salts include: inorganic acid salts such as hydrochlorides,hydrobromides, hydroiodides, sulfates and phosphates; sulfonates such asmethanesulfonates, benzenesulfonates and toluenesulfonates; carboxylatessuch as formates, acetates, oxalates, maleates, fumarates, citrates,malates, succinates, malonates, gluconates, mandelates, benzoates,salicylates, fluoroacetates, trifluoroacetates, tartrates, propionatesand glutarates; alkali metal salts such as lithium salts, sodium salts,potassium salts, cesium salts and rubidium salts; alkaline earth metalsalts such as magnesium salts and calcium salts; and ammonium salts suchas ammonium salts, alkylammonium salts, di alkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. Among them, alkali metalsalts such as lithium salts, sodium salts, potassium salts, cesium saltsand rubidium salts are preferred, and sodium salts and potassium saltsare particularly preferred.

The compound or pharmaceutically acceptable salt thereof according tothe present invention can be used for treatment of a cell proliferativedisorder, particularly cancer, by appropriately administering to thepatient a pharmaceutically effective amount thereof by itself or in theform of a pharmaceutical composition. As for the administration route,there may be used: systemic administration such as oral administration,rectal administration, intravenous administration, intramuscularadministration, subcutaneous administration, intracisternaladministration, vaginal administration, intraperitoneal administration,intravesical administration or inhalation administration; or topicaladministration in the form of an ointment, gel, cream or the like.

When the compound or pharmaceutically acceptable salt thereof accordingto the present invention is used in the form of a pharmaceuticalcomposition, it is generally prepared as a certain formulation (dosageform). As for the formulation, there may be mentioned, for example, atablet, a capsule, a granule, a powder, a fine granule, a pill, and anaqueous or nonaqueous solution and suspension. Furthermore, the compoundor salt may be used in the form of various controlled-releaseformulations, and as for the controlled-release formulation, there maybe mentioned, for example, a formulation used implanted in the body, anda formulation applied to the oral or nasal mucosa. The solution orsuspension may be stored filled in a container suited for thepreparation of a single dose.

Various formulations as mentioned above may be produced by a knownmethod, by mixing the compound or salt with a pharmaceuticallyacceptable additive. As for the additive, there may be mentioned anexcipient, a lubricant (coating agent), a binder, a disintegrant, astabilizer, a flavoring agent, a base, a dispersant, a diluent, asurfactant, an emulsifier, and the like.

As for the excipient, there may be mentioned, for example, starches(starch, potato starch, maize starch and the like), lactose, crystallinecellulose, and calcium hydrogen phosphate.

As for the lubricant (coating agent), there may be mentioned, forexample, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.

As for the binder, there may be mentioned, for example,polyvinylpyrrolidone and macrogol, as well as the same compounds asmentioned for the excipient.

As for the disintegrant, there may be mentioned, for example, chemicallymodified starches and celluloses, such as croscarmellose sodium, sodiumcarboxymethyl starch, and crosslinked polyvinylpyrrolidone, as well asthe same compounds as mentioned for the excipient.

As for the stabilizer, there may be mentioned, for example:paraoxybenzoic acid esters such as methylparaben and propylparaben;benzalkonium chloride; phenols such as phenol and cresol; thimerosal;dehydroacetic acid; and sorbic acid.

As for the flavoring agent, there may be mentioned, for example,sweeteners, acidulants and fragrances which are commonly used.

As for the base, there may be mentioned, for example: fats such as lard;vegetable oils such as olive oil and sesame oil; higher alcohols such asstearyl alcohol and cetanol; animal oils; lanolin acid; vaseline;paraffins; bentonite; glycerine; and glycol oils.

As for the dispersant, there may be mentioned, for example, cellulosederivatives (gum arabic, tragacanth, methyl cellulose and the like),stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate,sodium alginate, polysorbates, and sorbitan fatty acid esters.

As for the solvent or diluent in a liquid formulation, there may bementioned, for example, phenol, chlorocresol, purified water anddistilled water.

As for the surfactant or emulsifier, there may be mentioned, forexample, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

The preferred content of the compound or pharmaceutically acceptablesalt thereof according to the present invention in the formulationvaries depending on the dosage form, and is generally 0.01% to 100% byweight.

When the compound or pharmaceutically acceptable salt thereof accordingto the present invention is used as a therapeutic agent for a cellproliferative disorder, the dose can be appropriately determineddepending on the severity of symptom, age, body weight, relative healthcondition, presence or absence of concomitant drugs, administrationroute, and the like. For example, when the subject is a warm-bloodedanimal, particularly human, the dose per kilogram of body weight per dayfor oral administration is preferably 0.00001 to 5000 mg, morepreferably 0.0001 to 10 mg. The dose for parenteral administration isalso preferably 0.00001 to 5000 mg, more preferably 0.0001 to 10 mg. Thedose as mentioned above may be given once every day to once every 3weeks, or daily in 2 to 4 divided doses.

As described above, the compound or pharmaceutically acceptable saltthereof and pharmaceutical composition according to the presentinvention may be used as a therapeutic agent for a cell proliferativedisorder, particularly cancer. As for the cancer, there may bementioned, for example: blood cancers and lymphoid cancers, such asleukemias (acute myelocytic leukemia, acute lymphocytic leukemia,chronic myelocytic leukemia, chronic lymphocytic leukemia, and thelike), malignant lymphomas (Hodgkin's disease, non-Hodgkin's lymphoma,and the like), multiple myeloma, and myelodysplastic syndrome; and solidcancers, such as brain tumor, glioma, head and neck cancers (pharyngealcancer, laryngeal cancer, tongue cancer, and the like), esophagealcancer, gastric cancer, colorectal cancer, lung cancer (small cell lungcancer, non-small cell lung cancer, or the like), thyroid cancer, breastcancer, gallbladder cancer, pancreatic cancer, liver cancer, prostatecancer, ovarian cancer, uterine cancer, testicular cancer, renal cellcarcinoma, bladder cancer, renal pelvic and ureteral cancer, malignantmelanoma, and skin cancer.

As examples of the compound or pharmaceutically acceptable salt thereofaccording to the invention, there may be mentioned compounds representedby the following formulas and their pharmaceutically acceptable salts:

[where the combinations of G⁹, Y¹, Y², Y³, Y⁴, G¹, G², G³, Z¹⁹, G⁷ andR² are as listed in the table below.]

X G⁹ Y¹ Y² Y³ Y⁴ G¹ G² G³ Z¹⁹ G⁷ R² (CH₃)₂NCO O N N CH CH CH CH CHCH₂CH₂CH₃ CH₂ CH₃ (CH₃)₂NCO O N CH CH CH CH CH CH CH₂CH₃ CH₂ CH₃(CH₃)₂NCO O N CF CH CH CH N CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O N CF CH CHCH CH CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O N CF CH CH CH CF CH CH₂CH₃ CH₂CH₃ 2-Pyrimidinyl O N CF CH CH CH CCH₃ CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl OCH CF CH CH N CCH₃ CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CF CH CH CH N CHCH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CF CH CH CH N N CH₂CH₃ CH₂ CH₃2-Pyrimidinyl S N CH CH CH CH CH CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl NH N CHCH CH CH CH CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl CF₂ N CH CH CH CH CH CHCH₂CH₃ CH₂ CH₃ 2-Thiazolyl O N CF CH CH CH CCH₃ CH CH₂CH₃ CH₂ CH₃2-Thiazolyl O N N CH CH CH CCH₃ CH CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O CH CF CHCH CH N CH CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O CH CH N CH CH CCH₃ CH CH₂CH₃ CH₂CH₃ 2-Thiazolyl O CH CF CH N CH CCH₃ CH CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O NCF CH CH CH CH CH CH₂CH₃ S CH₃ 2-N-Methyl O CH CF CH CH CH N CH CH₂CH₃CH₂ CH₃ imidazolyl (CH₃)₂NCO O N CF CH CH CH CCH₃ CH CH₂CONHCH₃ CH₂ CH₃(CH₃)₂NCO O N CF CH CH CH CCH₃ CH CH₃ CH₂ CH₃ (CH₃)₂NCO O CH CF CH N CHCCH₃ CH CH₃ CH₂ CH₃ (CH₃)₂NCO O CH CF CH N CH CH CH CH₃ CH₂ CH₂CH₃(CH₃)₂NCO O CH CF CH CH CH N CH CH₃ CH₂ CH₃ (CH₃)₂NCO S N CF CH CH CH CHCH CH₃ CH₂ CH₃ (CH₃)₂NCO S N CF CH CH CH CH CH CH₃ S CH₃ (CH₃)₂NCO NH CHCF CH CH CH CH CH CH₃ O CH₃ 2-Thiazolyl S N CF CH CH CH CH CH CH₃ NH CH₃2-N-Methyl O N CF CH CH CH CH CH CH₃ CH₂ CH₃ imidazolyl[where the combinations of G⁹, Y¹, Y², Y³, Y⁴, Z¹⁶, Z¹⁷, Z¹⁸, G⁷ and R²are as listed in the table below.]

X G⁹ Y¹ Y² Y³ Y⁴ Z¹⁶ Z¹⁷ Z¹⁸ G⁷ R² 2-Pyrimidinyl O CH CH CH CH CH SCH₂CH₃ CH₂ CH₃ 2-Thiazolyl O CH CH CH CH CH S CH₂CH₃ CH₂ CH₃ 2-ThiazolylO N CF CH CH CH S CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O N N CH CH CH S CH₂CH₃ CH₂CH₃ (CH₃)₂NCO O N CF CH CH CH S CH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CF CH CHS CH CH₃ CH₂ CH₃ 2-Thiazolyl O CH CH CH CH S CH CH₃ CH₂ CH₃ 2-ThiazolylO N CF CH CH S CH CH₃ CH₂ CH₃ 2-N-Methyl O CH CF CH CH NH CH CH₃ CH₂ CH₃imidazolyl 2-N-Methyl O N CF N CH CH O CH₃ CH₂ CH₂CH₃ imidazolyl[where the combinations of G⁹, Z¹³, Z¹⁴, Z¹⁵, G¹, G², G³, Z¹⁶, G⁷ and R²are as listed in the table below.]

X G⁹ Z¹³ Z¹⁴ Z¹⁵ G¹ G² G³ Z¹⁶ G⁷ R² (CH₃)₂NCO O CH S CH CH CH CH CH₂CH₃CH₂ CH₃ (CH₃)₂NCO O N CH NH CH CH CH CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O CH SCH CH CH CH CH₂CH₃ O CH₃ 2-Thiazolyl O CH S CH N CH CH CH₂CH₃ CH₂ CH₃(CH₃)₂NCO O S CH CH CH N CH CH₃ CH₂ CH₃ (CH₃)₂NCO NH CH S CH CH N CH CH₃CH₂ CH₃ 2-Pyrimidinyl O S CH CH CH CH CH CH₃ CH₂ CH₃ 2-Pyrimidinyl O CHO CH CH CH CH CH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CH NH CH CH CH CH₃ CH₂ CH₃2-Thiazolyl O S CH CH CH CH CH CH₃ CH₂ CH₂CH₃ 2-Thiazolyl O CH CH S CHCH CH CH₃ CH₂ CH₃ 2-Thiazolyl O S CH CH CH N CH CH₃ S CH₂CH₃ 2-N-MethylO CH S CH CH N CH CH₃ CH₂ CH₃ imidazolyl[where the combinations of G⁹, Y¹, Y², Y³, Y⁴, Z¹⁶, Z¹⁷, NR⁶R⁷, G⁷ andR² are as listed in the table below.]

X G⁹ Y¹ Y² Y³ Y⁴ Z¹⁶ Z¹⁷ NR⁶R⁷ G⁷ R² 2-Thiazolyl O CH CH CH CH S CHN(CH₃)₂ CH₂ CH₃ 2-Thiazolyl O CH CH CH CH CH S NH₂ CH₂ CH₃ (CH₃)₂NCO OCH CH CH CH S CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH CH CH CH S NHCH₃ CH₂CH₃ (CH₃)₂NCO O N CF CH CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O N CH CH CH NHCH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH CH CH CH NH NHCH₃ CH₂ CH₃ (CH₃)₂NCO OCH CH CH CH O CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O N CF CH CH CH O NHCH₃ CH₂ CH₃(CH₃)₂NCO S CH CH CH CH S CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO S CH CH CH CH CH SNHCH₃ CH₂ CH₃ (CH₃)₂NCO NH CH CH CH CH S CH NHCH₃ CH₂ CH₂CH₃ (CH₃)₂NCONH CH CF CH CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH CH CH S N NHCH₃ CH₂CH₃ (CH₃)₂NCO O CH CH CH CH N S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH CH CH NN NHCH₃ CH₂ CH₂CH₃ (CH₃)₂NCO O CH CH CH CH N N NHCH₃ CH₂ CH₃2-Pyrimidinyl O CH CF CH CH S CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CH CHCH CH S NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O CH CH CH CH S CH NHCH₃ O CH₃2-Pyrimidinyl O CH CH CH CH CH S NHCH₃ S CH₃ 2-Pyrimidinyl O N CH CH CHS CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O N CF CH CH CH S NHCH₃ CH₂ CH₃2-Pyrimidinyl S CH CH CH CH NCH₃ CH NHCH₃ CH₂ CH₂CH₃ 2-Pyrimidinyl NH CHCH CH CH CH NCH₃ NHCH₃ CH₂ CH₃ 2-Thiazolyl O N CF CH CH O CH NHCH₃ CH₂CH₃ 2-Thiazolyl O N N CH CH CH O NHCH₃ CH₂ CH₂CH₃ 2-Thiazolyl O N N N CHCH S NHCH₃ CH₂ CH₃ 2-N-Methyl O N CF CH CH CH S NHCH₃ CH₂ CH₃ imidazolyl2-N-Methyl O N CF CH CH CH S NHCH₃ O CH₃ imidazolyl[where the combinations of G⁹, Z²³, Z²⁴, Z²⁵, Z²¹, Z²², Z²⁶, Z⁷ and R²are as listed in the table below.]

X G⁹ Z²³ Z²⁴ Z²⁵ Z²¹ Z²² Z²⁶ G⁷ R² (CH₃)₂NCO O S CH CH S CH NHCH₃ CH₂CH₃ (CH₃)₂NCO O S CH CH S CH CH₂CONHCH₃ CH₂ CH₃ (CH₃)₂NCO O S CH CH S CHCH₂CH₃ CH₂ CH₃ (CH₃)₂NCO O S CH CH S CH CH₂CH₂OH CH₂ CH₃ (CH₃)₂NCO O SCH CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH S CH S CH NHCH₃ CH₂ CH₃(CH₃)₂NCO O CH S CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH S S CH NHCH₃CH₂ CH₃ (CH₃)₂NCO O CH CH S CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O NH CH CH S CHNHCH₃ CH₂ CH₃ (CH₃)₂NCO O NH CH CH S CH CH₂CONHCH₃ CH₂ CH₃ (CH₃)₂NCO ONCH₃ CH CH S CH CH₂CH₃ CH₂ CH₃ (CH₃)₂NCO O NH CH CH S CH CH₂CH₂OH CH₂CH₃ (CH₃)₂NCO O NH CH CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO O NH CH CH CH SCH₃ CH₂ CH₃ (CH₃)₂NCO O CH NH CH S CH NHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH NH CHS CH CH₂CH₃ CH₂ CH₃ (CH₃)₂NCO O CH NH CH CH S NHCH₃ CH₂ CH₃ (CH₃)₂NCO OCH NH CH CH S CH₂CONHCH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH NH S CH NHCH₃ CH₂ CH₃(CH₃)₂NCO O CH CH NH S CH CH₂CH₃ CH₂ CH₃ (CH₃)₂NCO O CH CH NH CH S NHCH₃CH₂ CH₃ 2-Pyrimidinyl O S CH CH S CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S CHCH CH S NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S NH CH S CH NHCH₃ CH₂ CH₃2-Pyrimidinyl O S NH CH CH S NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S CH CH S NNHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S CH CH N S NHCH₃ CH₂ CH₃ 2-Pyrimidinyl ONH S CH S CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O NH S CH CH S NHCH₃ CH₂ CH₃2-Pyrimidinyl O N CH NH S CH NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O N CH NCH₃ CHS NHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S CH CH S CH CH₃ CH₂ CH₃ 2-Pyrimidinyl OS CH CH CH S CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O S NH CH S CH CH₂CH₂OH CH₂CH₃ 2-Pyrimidinyl O S NH CH CH S CH₂CONHCH₃ CH₂ CH₃ 2-Pyrimidinyl O S CHCH S N CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O S CH CH N S CH₂CH₃ CH₂ CH₃2-Pyrimidinyl O NH S CH S CH CH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O NH S CH CH SCH₂CH₃ CH₂ CH₃ 2-Pyrimidinyl O N CH NH S CH CH₂CH₃ CH₂ CH₃ 2-PyrimidinylO N CH NCH₃ CH S CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O CH O CH S CH NHCH₃ CH₂ CH₃2-Thiazolyl O CH O CH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O NH O CH S CHNHCH₃ CH₂ CH₃ 2-Thiazolyl O NH O CH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O NCH NH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O N CH NH S CH NHCH₃ CH₂ CH₃2-Thiazolyl O CH O CH NH CH NHCH₃ CH₂ CH₃ 2-Thiazolyl O CH O CH NCH₃ CHNHCH₃ CH₂ CH₃ 2-Thiazolyl S CH O CH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl NH CHO CH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl CH₂ NH O CH S CH NHCH₃ CH₂ CH₃2-Thiazolyl CF₂ NH O CH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl S N CH NH S CHNHCH₃ CH₂ CH₃ 2-Thiazolyl S N CH NH S CH NHCH₃ CH₂ CH₃ 2-Thiazolyl NH CHO CH NH CH NHCH₃ CH₂ CH₃ 2-Thiazolyl SO CH O CH NCH₃ CH NHCH₃ CH₂ CH₃2-Thiazolyl O CH O CH S CH NHCH₃ S CH₃ 2-Thiazolyl O CH O CH S CH NHCH₃NH CH₃ 2-Thiazolyl O NH O CH S CH NHCH₃ O CH₃ 2-Thiazolyl O NH O CH S CHCH₃ CH₂ CH₃ 2-Thiazolyl O N CH NH S CH CH₂CH₃ CH₂ CH₃ 2-Thiazolyl O N CHNH S CH CH₂CH₂OH CH₂ CH₃ 2-Thiazolyl O CH O CH NH CH CH₂CONHCH₃ CH₂ CH₃2-Thiazolyl O CH O CH NCH₃ CH CH₂CH₃ CH₂ CH₃ 2-N-Methyl O NH CH CH CH SNHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O S CH CH CH NH NHCH₃ CH₂ CH₃imidazolyl 2-N-Methyl O CH S CH CH NH NHCH₃ CH₂ CH₃ imidazolyl2-N-Methyl O CH CH S CH NH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O S CH CHN NH NHCH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O CH S CH N NH NHCH₃ CH₂ CH₃imidazolyl 2-N-Methyl O CH CH S N NH NHCH₃ CH₂ CH₃ imidazolyl 2-N-MethylO NH CH CH CH S CH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O S CH CH CH NH CH₂CH₃CH₂ CH₃ imidazolyl 2-N-Methyl O CH S CH CH NH CH₂CH₂OH CH₂ CH₃imidazolyl 2-N-Methyl O CH CH S CH NH CH₂CONHCH₃ CH₂ CH₃ imidazolyl2-N-Methyl O S CH CH N NH CH₂CH₃ CH₂ CH₃ imidazolyl 2-N-Methyl O N S CHN NH NHCH₃ CH₂ CH₃ imidazolyl

Exemplified embodiments of the present invention will now be describedmore specifically based on examples (manufacturing examples and testingexamples).

MANUFACTURING EXAMPLES

In the following manufacturing examples (synthetic examples), NMRanalysis was performed using JNM-EX270 (270 MHz) manufactured by JEOL,JNM-GSX400 (400 MHz) manufactured by the same, or ARX-300 (300 MHz)manufactured by Broker, NMR data were shown in ppm (parts per million,δ), and the deuterium lock signal from the sample solvent was used as areference.

Further, mass spectral data were obtained using JMS-DX303 manufacturedby JEOL, or IMS-SX/SX102A manufactured by the same, or using Micromass(Navigator manufactured by Finningan) equipped with gradient highperformance liquid chromatograph Agilent 1100 manufactured by AgilentTechnologies.

When reagents available on the market were used, they were used directlyin the reaction without pretreatment such as distillation orrecrystallization. The used reaction solvents were anhydrous when theyare available on the market.

In the meantime, all chemical reactions were performed under nitrogenatmosphere.

As used herein, “solvent was distilled away” means that solvent wasdistilled under reduced pressure using a rotary evaporator.

When a compound of sufficiently high purity cannot be obtained bystandard synthesis protocols, separation and purification by silica gelchromatography, alumina gel chromatography or the like may be carriedout as necessary to obtain a compound of higher purity.

(General Process-1)

First, manufacturing examples associated with General process-1previously mentioned will be explained.

Compound 1c-2 2-(2-Fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester

Ethyl acetoacetate (37.4 mL, 294 mmol) was added at 0° C. to asuspension of sodium hydride (65%, 10.8 g) in THF (600 mL), and themixture was stirred at 0° C. for 30 minutes. It was added dropwise at 0°C. to a solution of 1-bromomethyl-2-fluoro-3-nitrobenzene (compound1a-1) (68.7 g, 294 mmol) in THF (400 mL), and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was thenpoured into 0.5N hydrochloric acid and extracted with ethyl acetate. Theorganic extract was washed with saturated saline and dried overmagnesium sulfate. A crude product was obtained by vacuum concentration,and purified by column chromatography (ethyl acetate:hexane=1:3) toyield the title compound (52.2 g, 63%) as a yellow oil.

¹H NMR (DMSO-d₆, 270 MHz) (ketone body) δ (ppm): 8.01 (td, J=7.6, 1.9Hz, 1H), 7.72 (td, J=7.2, 1.9 Hz, 1H), 7.37 (td, J=7.5, 1.1 Hz, 1H),4.11 (m, 1H), 4.07(qd, J=7.0, 1.0 Hz, 2H), 3.16 (t, J=7.3 Hz, 2H), 2.23(s, 3H), 1.10 (t, J=7.0 Hz, 3H).

ESIMS m/z: 284 (M+H).

Compound 1c-1 2-(3-Nitrobenzyl)-3-oxobutanoic acid ethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that1-bromomethyl-3-nitrobenzene was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.08 (3H, t, J=6.8 Hz), 2.25 (3H, s),3.17 (2H, m), 4.05 (2H, qd, J=6.8, 2.7 Hz), 4.16 (1H, m), 7.58 (1H, dd,J=8.1 Hz), 7.71 (1H, d, J=8.1 Hz), 8.08 (1H, d, J=8.1 Hz), 8.14 (1H, s).

ESI (LC/MS positive mode) m/z: 266 (M+H).

Compound 1c-3 2-(2-Methyl-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that1-chloromethyl-2-methyl-3-nitrobenzene was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.62 (1H, d, J=8.0 Hz), 7.37(1H, d, J=7.2 Hz), 7.23 (1H, m), 4.16 (2H, q), 3.73 (1H, t, J=7.4 Hz),3.28 (2H, m), 2.43 (3H, s), 2.24 (3H, s), 1.21 (3H, t, J=7.1 Hz).

Compound 1c-46 2-(4-Nitrobenzyl)-3-oxobutanoic acid ethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that1-bromomethyl-4-nitrobenzene was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.14 (2H, d, J=8.7 Hz), 7.36(2H, d, J=8.7 Hz), 4.17 (2H, m), 3.79 (1H, t, J=7.6 Hz), 3.25 (2H, m),2.24 (3H, s), 1.22 (3H, m).

Compound 1c-45 2-(2-Nitrobenzyl)-3-oxobutanoic acid ethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that1-bromomethyl-2-nitrobenzene was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.00 (1H, d, J=8.4 Hz),7.52-7.42 (3H, m), 4.22-4.09 (2H, m), 4.01 (1H, q), 3.54-3.32 (2H, m),2.28 (3H, s), 1.20 (3H, t, J=7.1 Hz).

Compound 1c-36 2-(4-Fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that1-bromomethyl-3-nitro-4-fluorobenzene was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.07 (dd, 1H, J=7.1, 2.2 Hz), 7.67(m, 1H), 7.52 (dd, 1H, J=10.7, 8.6 Hz), 4.11 (m, 1H), 4.07 (q, 2H, J=7.0Hz), 3.20 (m, 2H), 2.21 (s, 3H), 1.13 (t, 3H, J=7.0 Hz).

ESIMS m/z: 284 (M+H).

Compound 1c-51a3-(Methoxycarbonylhydrazono)-2-(3-nitrophenylamino)butanoic acid ethylester

3-Nitroaniline (2.92 g, 21.27 mmol) was added to a solution of ethyl3-carbomethoxyazocrotonate (4.2 g, 21.13 mmol) (which is known in theliterature) in THF (40 mL), and the mixture was stirred at 70° C. for aday and a night. After cooling to room temperature, hexane was addedthereto, and the deposited precipitate was filtered out to yield thetitle compound (5.08 g, 71%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.10 (s, 1H), 7.55 (s, 1H),7.46-7.31 (m, 2H), 7.11 (d, 1H, J=8.1 Hz), 6.96 (d, 1H, J=7.4 Hz), 4.94(d, 1H, J=7.7 Hz), 4.18 (q, 2H, J=7.1 Hz), 3.67 (s, 3H), 1.83 (s, 3H),1.21 (t, 3H, J=7.1 Hz).

ESIMS m/z: 339 (M+H).

Compound 1c-51 2-(3-Nitrophenylamino)-3-oxobutanoic acid ethyl ester

Titanium trichloride (10% solution in 20-30% HCl) was added to asolution of 3-(methoxycarbonylhydrazono)-2-(3-nitrophenylamino)butyricacid ethyl ester (compound 1c-51a) (5.0 g, 14.78 mmol) in acetone (50mL), and the mixture was stirred at room temperature for 1 hour. Waterwas then added to the reaction mixture, extraction was performed withethyl acetate, and the organic extract was washed with water andsaturated saline. After drying over magnesium sulfate, it wasconcentrated under reduced pressure to yield a crude product, which wasthen purified by column chromatography to yield the title compound (3.75g, 95%) as a yellow oil.

¹H NMR (270 MHz, DMSO-d₆) (2:1 mixture of keto and enol forms) δ (ppm):12.37 (s, 1/3H), 7.53 (t, 2/3H, J=2.2 Hz), 7.47-7.37 (m, 10/3H), 7.27(t, 1/3H, J=2.2 Hz), 7.13 (m, 2/3H), 7.05 (d, 2/3H, J=8.6 Hz), 6.92 (d,1/3H, J=9.1 Hz), 5.35 (d, 2/3H, J=8.6 Hz), 4.25-4.11 (m, 6/3H), 2.31 (s,6/3H), 1.99 (s, 3/3H), 1.21 (t, 6/3H, J=7.1 Hz), 1.08 (t, 3/3H, J=7.1Hz).

ESIMS m/z: 267 (M+H).

Compound 1c-59 2-(2-Nitrobenzoylamino)-3-oxobutanoic acid ethyl ester(Known Compound)

Rh₂(OAc)₄ (30 mg, 0.063 mmol) was added to a solution of ethyldiazoacetoacetate (1.0 g, 6.32 mmol) and 2-nitrobenzamide (1.05 g, 6.32mmol) in methylene chloride (15 mL), and the mixture was stirred at 40°C. for a day and a night. Water was then added to the reaction mixture,extraction was performed with ethyl acetate, and the organic extract waswashed with water and saturated saline. After drying over magnesiumsulfate, it was concentrated under reduced pressure to yield a crudeproduct, which was then purified by column chromatography to yield thetitle compound (1.42 g, 77%) as a yellow oil.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.58 (d, 1H, J=7.4 Hz), 8.09 (d, 1H,J=7.9 Hz), 7.84 (td, 1H, J=7.5, 0.5 Hz), 7.73 (td, 1H, J=7.8, 1.2 Hz),7.63 (dd, 1H, J=7.4, 1.5 Hz), 5.39 (d, 1H, J=7.6 Hz), 4.21 (m, 2H), 2.30(s, 3H), 1.24 (t, 3H, J=7.3 Hz).

ESIMS m/z: 295 (M+H).

Compound 1c-73 2-(5-Nitro-thiophen-2-ylmethyl)-3-oxobutanoic acid ethylester

Ethyl acetoacetate (0.64 mL, 5.06 mmol) was added to a mixture of sodiumiodide (379 mg, 2.53 mmol) with tetrahydrofuran. A solution of 1 MLiOtBu in THF (3.03 mL, 3.03 mmol) was added thereto at 4° C., and themixture was stirred for 30 minutes. A solution of compound 1a-73 (600mg, 2.53 mmol) in tetrahydrofuran (2.0 mL) was then added at 4° C., andthe mixture was raised to room temperature and stirred for 22 hours.Water (20 mL) was added, and the organic layer was extracted with ethylacetate. It was then purified by silica gel chromatography (hexane:ethylacetate=6:1) to yield the title compound (623 mg, 91%).

¹H-NMR (Bruker (ARX300), 300 MHz, CDCl₃) δ (ppm): 7.79 (1H, d, J=4.20Hz), 6.85 (1H, d, J=4.20 Hz), 4.27 (2H, q), 3.84 (1H, t, J=6.87 Hz),3.41 (2H, dd, J=6.87, 7.25 Hz), 2.34 (3H, s), 1.32 (3H, t, J=6.87 Hz).

Compound 1e-0-43-(2-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Concentrated sulfuric acid (21.5 mL) was added at 0° C. to a mixture ofresorcinol (14.8 g, 135 mmol) and2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoic acid ethyl ester (38.2 g, 135mmol), and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was then poured into water, and thesolid was filtered off. It was washed with water and methanol to yieldthe title compound (28.3 g, 64%) as a pale yellow powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 7.98 (td, J=8.9, 1.6 Hz, 1H), 7.69(d, J=8.9 Hz, 1H), 7.58 (td, J=6.2, 4.3 Hz, 1H), 7.32 (td, J=8.9, 1.1Hz, 1H), 6.83 (dd, J=8.9, 2.4 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 4.02 (s,2H), 2.43 (s, 3H).

ESIMS m/z: 330 (M+H).

Compound 1e-0-13-(3-Nitrobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using resorcinol and compound 1c-1under the same conditions as in the manufacturing example for compound1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 4.08 (2H, s), 6.72 (1H,d, J=1.9 Hz), 6.82 (1H, dd, J=1.9, 8.6 Hz), 7.58 (1H, dd, J=7.8, 7.8Hz), 7.66-7.72 (2H, m), 8.05-8.08 (2H, m).

ESI (LC/MS positive mode) m/z: 312 (M+H).

Compound 1e-0-23-(3-Nitrobenzyl)-7-hydroxy-4-methyl-6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized using 4-fluororesorcinol and compound1c-1 under the same conditions as in the manufacturing example forcompound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.43 (3H, s), 4.13 (2H, s), 6.71 (2H,d, J=7.6 Hz), 7.55-7.71 (3H, m), 8.05-8.07 (2H, m), 10.51 (1H, s).

ESI (LC/MS positive mode) m/z: 330 (M+H).

Compound 1e-0-33-(3-Nitrobenzyl)-7-hydroxy-4-methyl-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized using 4-chlororesorcinol and compound1c-1 under the same conditions as in the manufacturing example forcompound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.48 (3H, s), 4.09 (2H, s), 6.90 (1H,s), 7.55 (1H, t, J=7.7 Hz), 7.70 (1H, d, J=7.7 Hz), 7.81 (1H, s), 8.05(1H, d, J=7.7 Hz), 8.06 (1H, s).

ESI (LC/MS positive mode) m/z: 346 (M+H).

Compound 1e-0-53-(2-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized using 4-fluororesorcinol and compound1c-2 under the same conditions as in the manufacturing example forcompound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 4.03 (2H, s), 6.92 (1H,d, J=7.6 Hz), 7.32 (1H, dd, J=7.7, 8.6 Hz), 7.57 (1H, dd, J=7.7, 6.3Hz), 7.69 (1H, d, J=12.0 Hz), 7.99 (1H, dd, J=6.9, 8.6 Hz), 11.07 (1H,brs).

ESI (LC/MS positive mode) m/z: 347 (M+H).

Compound 1e-0-63-(2-Methyl-3-nitrobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using resorcinol and compound 1c-3under the same conditions as in the manufacturing example for compound1e-0-4.

¹H NMR (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 10.51 (1H, s), 7.69 (1H, d,J=8.8 Hz), 7.65 (1H, d, J=8.0 Hz), 7.27 (1H, t, J=8.0 Hz), 7.12 (1H, d,J=7.6 Hz), 6.84 (1H, dd, J=2.3, 8.8 Hz), 6.74 (1H, d, J=2.3 Hz), 3.95(2H, s), 2.42 (3H, s), 2.33 (3H, s).

Compound 1e-0-73-(3-Nitrobenzyl)-7-hydroxy-4-methyl-6-iodo-2-oxo-2H-1-benzopyran

The title compound was synthesized using 4-iodoresorcinol and compound1c-1 under the same conditions as in the manufacturing example forcompound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 4.07 (2H, s), 6.82 (1H,s), 7.57 (1H, dd, J=5.4, 5.4 Hz), 7.69 (1H, d, J=2.7 Hz), 8.05-8.10 (3H,m), 11.39 (1H, s).

ESI (LC/MS positive mode) m/z: 437 (M+H).

Compound 1e-0-83-(3-Nitrobenzyl)-7-hydroxy-4-methyl-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using 4-methylresorcinol and compound1c-1 under the same conditions as in the manufacturing example forcompound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.19 (3H, s), 2.44 (3H, s), 4.07 (2H,s), 6.74 (1H, s), 7.53-7.61 (2H, m), 7.69 (1H, d, J=7.9 Hz), 8.02-8.09(2H, m), 10.50 (1H, s).

ESI (LC/MS positive mode) m/z: 326 (M+H).

Compound 1e-0-363-(4-Fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1e-0-4, except that compound 1c-36was used instead of compound 1c-2.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.98 (dd, 1H, J=7.1, 2.2 Hz),7.69-7.61 (m, 2H), 7.49 (dd, 1H, J=10.7, 8.6 Hz), 6.82 (dd, 1H, J=8.9,2.4 Hz), 6.72 (d, 1H, J=2.4 Hz), 4.07 (s, 2H), 2.38 (s, 3H).

ESIMS m/z: 371 (M+H).

Compound 1e-0-46 3-(4-Nitrobenzyl)-7-hydroxy-4-methyl-2H-1-benzopyran

The title compound was synthesized using resorcinol and compound 1c-46under the same conditions as in the manufacturing example for compound1e-0-4.

¹H-NMR (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 10.48 (1H, s), 8.13 (2H, d,J=8.4 Hz), 7.66 (1H, d, J=8.8 Hz), 7.50 (2H, d, J=8.4 Hz), 6.82 (1H, dd,J=2.3, 8.8 Hz), 6.72 (1H, d, J=2.3 Hz), 4.06 (2H, s), 2.41 (3H, s).

Compound 1e-0-453-(2-Nitrobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using resorcinol and compound 1c-45under the same conditions as in the manufacturing example for compound1e-0-4.

¹H-NMR (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 10.55 (1H, s), 7.97 (1H, d,J=8.0 Hz), 7.69 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=7.6 Hz), 7.46 (1H, t,J=7.6 Hz), 7.20 (1H, d, J=7.6 Hz), 6.83 (1H, dd, J=2.3, 8.8 Hz), 6.72(1H, d, J=2.3 Hz), 4.17 (2H, s), 2.37 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 311.76 (M+H).

Compound 1e-0-47 4,7-Dihydroxy-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran

4,7-Dihydroxy-2-oxo-2H-1-benzopyran (500 mg, 2.81 mmol) and3-nitrobenzaldehyde (424 mg, 2.81 mmol) were added to a mixture oftriethylamine (1.57 mL, 11.23 mmol) and formic acid (1.07 mL, 28.07mmol), and the obtained mixture was stirred at 100° C. for 2 hours. A 5Nhydrochloric acid aqueous solution was added to the reaction mixture,and extraction was performed with ethyl acetate. The organic extract waswashed with saturated saline and dried over magnesium sulfate, and thenconcentrated under reduced pressure to yield the title compound (300 mg,34%) as a pale yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.52 (s, 1H), 8.09-8.04 (m, 2H),7.83 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=7.6 Hz), 7.57 (t, 1H, J=7.7 Hz),6.80 (dd, 1H, J=9.0, 2.4 Hz), 6.69 (d, 1H, J=2.0 Hz), 3.95 (s, 2H).

ESIMS m/z: 314 (M+H).

Compound 1e-0-517-Hydroxy-4-methyl-3-(3-nitrophenylamino)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1e-0-4, except that2-(3-nitrophenylamino)-3-oxobutanoic acid ethyl ester (compound 1c-51)was used instead of compound 1c-2.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.50 (s, 1H), 8.13 (s, 1H), 7.65 (d,1H, J=8.7 Hz), 7.51 (d, 1H, J=9.1 Hz), 7.42-7.34 (m, 2H), 7.01 (d, 1H,J=7.3 Hz), 6.86 (dd, 1H, J=8.7, 2.3 Hz), 6.77 (d, 1H, J=2.3 Hz), 2.29(s, 3H).

ESIMS m/z: 313 (M+H).

Compound 1e-0-592-Nitro-N-(7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl)benzamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1e-0-4, except that compound 1c-59was used instead of compound 1c-2.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.68 (s, 1H), 10.26 (s, 1H), 8.12(d, 1H, J=7.7 Hz), 7.89 (t, 1H, J=6.3 Hz), 7.80-7.74 (m, 3H), 7.71 (d,1H, J=8.7 Hz), 6.88 (dd, 1H, J=8.4, 2.3 Hz), 6.77 (d, 1H, J=2.3 Hz),2.40 (s, 3H).

ESIMS m/z: 341 (M+H).

Compound 1e-0-727-Hydroxy-4-methyl-3-(3-nitrobenzyl)-pyrano[2,3-b]pyridin-2-one

Zn(OTf)₂ (669 mg, 1.84 mmol) was added to a suspension ofpyridine-2,6-diol (204 mg, 1.84 mmol) and 2-(3-nitrobenzyl)-3-oxobutyricacid ethyl ester (488 mg, 1.84 mmol) in methanol (10 mL), and themixture was stirred at 75° C. for 30 hours. The reaction mixture wasthen poured into water and extracted with ethyl acetate. The organicextract was washed with saturated saline and dried over magnesiumsulfate. It was then concentrated under reduced pressure to yield acrude product, which was then purified by column chromatography to yieldthe title compound (330 mg, 57%).

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 4.07 (2H, s), 6.67 (1H,d, J=8.6 Hz), 7.57 (1H, dd, J=7.7, 7.9 Hz), 7.71 (1H, d, J=7.7 Hz),8.05-8.14 (3H, m).

ESI (LC/MS positive mode) m/z: 313 (M+H).

Compound 1e-0-733-(5-Nitro-thiophen-2-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 1c-73 under the sameconditions as in the manufacturing example for compound 1e-0-4.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 10.58 (1H, s), 7.98(1H, d, J=4.20), 7.68 (1H, d, J=8.77 Hz), 7.11 (1H, d, J=4.20 Hz), 6.82(1H, dd, J=8.77 Hz), J=1.91 Hz), 6.72 (1H, d, J=2.29 Hz), 4.17 (2H, s),2.47 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 315.83 (M−1).

Compound 1g-1-5 Dimethylcarbamic acid2-oxo-2H-3-(2-fluoro-3-nytrobenzyl)-4-methyl-6-fluoro-1-benzopyran-7-ylester

Sodium hydride (60%, 46.2 mg, 1.16 mmol) was added to a solution ofcompound 1e-0-5 (364.9 mg, 1.05 mmol) in THF (4 mL), and the mixture wasstirred at room temperature for 5 minutes. N,N-dimethylcarbamoylchloride (116 μL, 1.26 mmol) was added thereto, and the mixture wasstirred at room temperature for 1 hour. Aqueous saturated ammoniumchloride solution (2 mL) was then added to the reaction solution, andprecipitates were recovered by filtration. The precipitates were thenwashed with water to yield the title compound (407.8 mg, 93%) as a whitesolid.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 4.07 (2H, s), 7.31-7.34 (1H, m), 7.49 (1H, d, J=6.8 Hz), 7.59-7.63(1H, m), 7.89 (1H, d, J=11.4 Hz), 7.99 (1H, dd, J=6.9, 8.24 Hz).

ESI (LC/MS positive mode) m/z: 419 (M+H).

Compound 1g-1-1 Dimethylcarbamic acid4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-1was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.12 (s, 1H), 8.07 (d, J=8.2 Hz, 1H),7.86 (d, J=8.7 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H),7.26 (d, J=2.3 Hz, 1H), 7.19 (dd, J=8.7, 2.5 Hz, 1H), 4.14 (s, 2H), 3.07(s, 3H), 2.93 (s, 3H), 2.51 (s, 3H).

ESIMS m/z: 383 (M+H).

Compound 1g-1-2 Dimethylcarbamic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-fluoro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-2was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.50 (3H, s), 2.94 (3H, s), 3.08 (3H,s), 4.14 (2H, s), 7.49 (1H, d, J=6.8 Hz), 7.58 (1H, dd, J=7.9, 7.9 Hz),7.72 (1H, d, J=7.9 Hz), 7.86 (1H, d, J=11.1 Hz), 8.08 (1H, m), 8.12 (1H,s).

ESI (LC/MS positive mode) m/z: 419 (M+H).

Compound 1g-1-3 Dimethylcarbamic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-chloro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-3was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.12 (s, 1H), 8.08 (d, J=8.2 Hz, 1H),8.02 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.58 (t, J=8.2 Hz, 1H), 7.50 (s,1H), 4.14 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.51 (s, 3H).

ESIMS m/z: 417 (M+H).

Compound 1g-1-4 Dimethylcarbamic acid2-oxo-2H-3-(2-fluoro-3-nitrobenzyl)-4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-4was used instead of compound 1e-0-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.07 (3H, s), 4.08 (2H,s), 7.20 (1H, dd, J=8.7, 2.3 Hz), 7.26 (1H, d, J=2.3 Hz), 7.31 (1H, td,J=8.3, 2.3 Hz), 7.60 (1H, ddd, J=8.3, 6.5, 1.8 Hz), 7.88 (1H, d, J=8.7Hz), 7.99 (1H, ddd, J=8.3, 6.5, 1.8 Hz).

ESI (LC/MS positive mode) m/z: 401 (M+1H)

Compound 1g-1-7 Dimethylcarbamic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-iodo-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-7was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.96 (3H, s), 3.13 (3H, s), 4.13 (2H,s), 7.38 (1H, s), 7.57 (1H, dd, J=7.7, 8.1 Hz), 7.71 (1H, d, J=7.7 Hz),8.08 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.24 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 509 (M+H).

Compound 1g-1-8 Dimethylcarbamic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-8was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.23 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 4.13 (2H, s), 7.22 (1H, s), 7.57 (1H, dd, J=7.4, 8.1 Hz), 7.71 (1H,d, J=7.4 Hz), 7.76 (1H, s), 8.08 (1H, d, J=8.1 Hz), 8.10 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 397 (M+H).

Compound 1g-1-9 Dimethylcarbamic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-cyano-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-9was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.99 (3H, s), 3.14 (3H, s), 4.12 (2H,s), 7.38 (1H, s), 7.57 (1H, dd, J=7.7, 8.1 Hz), 7.71 (1H, d, J=7.7 Hz),8.08 (1H, d, J=8.1 Hz), 8.11 (1H, s), 8.24 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 408 (M+H).

Compound 1g-1-38 Dimethylcarbamic acid6-carbamoyl-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

Acetic acid (5 mL) and concentrated sulfuric acid (5 mL) were added tocompound 1g-1-9 (1.2 g, 2.95 mmol), and the mixture was stirred at roomtemperature for 1.5 hours. The reaction mixture was poured into sodiumhydrogen carbonate solution and extracted with ethyl acetate. Theorganic extract was washed with saturated saline and dried overmagnesium sulfate. It was then concentrated under reduced pressure toyield a crude product, which was then purified by column chromatographyto yield the title compound (1.1 g, 90%).

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.90 (3H, s), 3.06 (3H, s), 4.15 (2H,s), 7.29 (1H, s), 7.50 (1H, brs), 7.55-7.61 (2H, m), 7.70-7.73 (2H, m),7.80 (1H, brs), 8.01 (1H, s).

One of the methyl peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 426 (M+H).

Compound 1g-1-39 Dimethylcarbamic acid3-(3-nitrobenzyl)-4-methyl-2-oxo-6-trimethylsilanylethynyl-2H-1-benzopyran-7-ylester

Compound 1g-1-7 (1.45 g, 2.85 mmol),bis(triphenylphosphine)palladium(II) dichloride (100 mg, 0.143 mmol),copper(I) iodide (55 mg, 0.29 mmol), trimethylsilylacetylene (1.4 g,14.3 mmol) and diisopropylethylamine (550 μL, 3.2 mmol) were mixed with10 mL of anhydrous tetrahydrofuran, and the mixture was heated andstirred at 45 to 55° C. for 10 hours. It was then purified by silica gelchromatography (elution with methylene chloride) to yield 1.06 g of thetitle compound.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.21 (9H, s), 2.94 (3H, s), 3.08 (3H,s), 4.13 (2H, s), 7.39 (1H, s), 7.57 (1H, t, J=8.0 Hz), 7.70 (1H, d,J=8.0 Hz), 7.94 (1H, s), 8.06 (1H, d, J=8.0 Hz), 8.12 (1H, s).

One of the methyl peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 449 (M+H).

Compound 1g-1-59 Dimethylcarbamic acid3-(2-nitrobenzoylamino)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-59was used instead of compound 1e-0-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.44 (s, 1H), 8.13 (d, 1H, J=7.7Hz), 7.92-7.88 (m, 2H), 7.80-7.76 (m, 2H), 7.33 (d, 1H, J=2.1 Hz), 7.25(dd, 1H, J=8.7, 2.3 Hz), 3.08 (s, 3H), 2.92 (s, 3H), 2.46 (s, 3H).

ESIMS m/z: 412 (M+H).

Compound 1g-1-72 Dimethylcarbamic acid4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-72was used instead of compound 1e-0-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.95 (3H, s), 3.07 (3H, s), 4.14 (2H,s), 7.28 (1H, d, J=8.4 Hz), 7.58 (1H, dd, J=7.7, 8.1 Hz), 7.73 (1H, d,J=7.7 Hz), 8.05-8.14 (2H, m), 8.43 (1H, d, J=8.4 Hz).

The CH₃ peak was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 384 (M+H).

Compound 1g-1b-17-Isobutoxy-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-1was used instead of compound 1e-0-4, and that isopropyl bromide was usedinstead of bromopyrimidine.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 0.98 (3H, s), 1.00 (3H, s), 1.95-2.11(1H, m), 2.47 (3H, s), 3.86 (2H, d, J=6.5 Hz), 4.10 (2H, s), 6.93-7.06(2H, m), 7.58 (1H, dd, J=8.1, 7.8 Hz), 7.64-7.79 (2H, m), 8.00-8.11 (2H,m).

ESI (LC-MS positive mode) m/z: 368 (M+H).

p-Toluenesulfonic acid 2-fluoroethyl ester

1 g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL),and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over aperiod of 30 minutes while stirring on ice. The mixture was stirred at0° C. under nitrogen atmosphere for 3 hours, and after adding 35 mL ofice water to the reaction mixture, extraction was performed with 30 mLof ethyl acetate. The obtained organic layer was washed three times with30 mL of 1 N hydrochloric acid, and then further washed with sodiumcarbonate solution and saturated saline. The obtained organic layer wasdried over anhydrous sodium sulfate, and the solvent was distilled awayunder reduced pressure to yield the title compound (3.19 g, 94%) as acolorless oil.

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 2.46 (3H, s), 4.14-4.25 (1H, m),4.25-4.36 (1H, m), 4.43-4.36 (1H, m), 4.61-4.71 (1H, m), 7.36 (2H, d,J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz).

Compound 1g-1c-17-(2-Fluoroethoxy)-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-1was used instead of compound 1e-0-4, and that p-toluenesulfonic acid2-fluoroethyl ester was used instead of bromopyrimidine.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.43 (3H, s), 4.10 (2H, s), 4.29-4.36(1H, m), 4.39-4.46 (1H, m), 4.64-4.71 (1H, m), 4.82-4.89 (1H, m),6.96-7.07 (2H, m), 7.58 (1H, dd, J=8.1, 7.6 Hz), 7.71 (1H, d, J=8.1 Hz),7.78 (1H, d, J=8.6 Hz), 8.01-8.11 (2H, m).

Compound 1g-1c-36-Chloro-7-(2-fluoroethoxy)-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-3was used instead of compound 1e-0-4, and that p-toluenesulfonic acid2-fluoroethyl ester was used instead of bromopyrimidine.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.43 (3H, s), 4.11 (2H, s), 4.36-4.43(1H, m), 4.46-4.54 (1H, m), 4.68-4.73 (1H, m), 4.86-4.91 (1H, m), 7.30(1H, s), 7.58 (1H, dd, J=8.1, 7.8 Hz), 7.71 (1H, d, J=8.1 Hz), 7.93 (1H,s), 8.04-8.11 (2H, m).

Compound 1g-1d-1 Pyrrolidine-1-carboxylic acid4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that 1e-0-1 was usedinstead of compound 1e-0-5, and that pyrrolidine-1-carbonyl chloride wasused instead of N,N-carbamic acid chloride.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 1.93-2.02 (4H, m), 2.49 (3H, s), 3.50(2H, t, J=6.6 Hz), 3.59 (2H, t, J=6.6 Hz), 4.15 (2H, s), 7.14-7.19 (2H,m), 7.45 (1H, t, J=7.8 Hz), 7.61-7.65 (2H, m), 8.06-8.10 (2H, m)

ESI (LC/MS positive mode) m/z: 409 (M+H).

Compound 1g-2-44-Methyl-3-(2-fluoro-3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

Compound 1e-0-4 (15 g, 45.6 mmol) and 2-bromopyrimidine (72.4 g, 455mmol) were dissolved in N,N-dimethylformamide (300 mL), and potassiumcarbonate (12.6 g, 91.2 mmol) was added thereto. The mixture was stirredat 80° C. under nitrogen atmosphere for 1 hour. Ethyl acetate was thenadded to the reaction solution, and the solution was washed with sodiumhydrogen carbonate solution, water and saturated saline. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasdistilled away under reduced pressure. The resultant residue waspurified by silica gel column chromatography (hexane:ethyl acetate=1:2)to yield the title compound (10.57 g, 57%) as a pale yellow powder.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.52 (3H, s), 4.10 (2H, s), 7.28 (1H,dd, J=8.8, 2.4 Hz), 7.30-7.36 (2H, m), 7.38 (1H, d, J=2.4 Hz), 7.59-7.64(1H, m), 7.93 (1H, d, J=8.8 Hz), 7.97-8.03 (1H, m), 8.69 (2H, d, J=4.4Hz).

ESI (LC/MS positive mode) m/z: 408 (M+H).

Compound 1g-2-14-Methyl-3-(3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-1was used instead of compound 1e-0-4.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.52 (3H, s), 4.17 (2H, s), 7.12 (1H,t, J=4.8 Hz), 7.20 (1H, dd, J=2.1, 8.7 Hz), 7.20-7.40 (1H, m), 7.46 (1H,dd, J=7.7, 7.7 Hz), 7.64 (1H, d, J=7.7 Hz), 7.72 (1H, d, J=8.7 Hz),8.07-8.10 (2H, m), 8.59 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 390 (M+H).

Compound 1g-2-34-Methyl-3-(3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-6-chrolo-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-3was used instead of compound 1e-0-4.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.51 (3H, s), 4.16 (2H, s), 7.13 (1H,t, J=4.8 Hz), 7.29 (1H, s), 7.45 (1H, t, J=7.7 Hz), 7.62 (1H, d, J=7.7Hz), 7.75 (1H, s), 8.06 (1H, d, J=7.7 Hz), 8.07 (1H, brs), 8.60 (2H, d,J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 424 (M+H).

Compound 1g-2-474-Hydroxy-3-(3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 1e-0-47was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 8.12 (m, 1H),8.09-8.03 (dd, 2H), 7.73 (d, 1H, J=7.7 Hz), 7.57 (t, 1H, J=7.9 Hz),7.35-7.32 (m, 2H), 7.25 (dd, 1H, J=9.0, 2.2 Hz), 4.00 (s, 2H).

ESIMS m/z: 392 (M+H).

Compound 1g-3-34-Methyl-3-(3-nitrobenzyl)-7-(thiazol-2-yloxy)-6-chrolo-2-oxo-2H-1-benzopyran

Compound 1e-0-3 (2.0 g, 5.78 mmol) was dissolved inN,N-dimethylformamide (10 mL), and 2-bromothiazole (2.1 mL, 23.1 mmol),cesium carbonate (3.8 g, 11.6 mmol) and copper(I) iodide (220 mg, 1.16mmol) were added thereto. The mixture was stirred at 110° C. for 1 hourwhile irradiating microwave (100 W). Ethyl acetate was then added to thereaction solution, and the solution was washed with water and saturatedsaline. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was distilled away under reduced pressure. The resultantresidue was purified by silica gel column chromatography(dichloromethane:methanol=20:1) to yield the title compound (496 mg,20%) as a pale yellow powder.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.50 (3H, s), 4.15 (2H, s), 6.94 (1H,d, J=3.8 Hz), 7.23 (1H, d, J=3.8 Hz), 7.44-7.50 (2H, m), 7.60-7.63 (1H,m), 7.75 (1H, s), 8.07-8.10 (2H, m).

ESI (LC/MS positive mode) m/z: 429 (M+H).

Compound 1g-3-14-Methyl-3-(3-nitrobenzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-3-3, except that compound 1e-0-1was used instead of compound 1e-0-3.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.50 (3H, s), 4.15 (2H, s), 6.93 (1H,d, J=3.8 Hz), 7.26-7.34 (3H, m), 7.43-7.50 (1H, m), 7.61-7.66 (1H, m),7.68 (1H, d, J=8.8 Hz), 8.05-8.10 (2H, m).

ESI (LC/MS positive mode) m/z: 395 (M+H).

Compound 1g-3-84-Methyl-3-(3-nitrobenzyl)-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-3-3, except that compound 1e-0-8was used instead of compound 1e-0-3.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.28 (3H, s), 4.14 (2H, s), 7.29 (2H,s), 7.45 (1H, s), 7.58 (1H, dd, J=7.4, 8.2 Hz), 7.72 (1H, d, J=7.4 Hz),7.87 (1H, s), 8.08 (1H, d, J=8.2 Hz), 8.11 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 409 (M+H).

Compound 1g-11-34-Methyl-3-(3-nitrobenzyl)-7-(thiophen-3-yl)-6-chloro-2-oxo-2H-1-benzopyran

The compound trifluorosulfonic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-chloro-1-benzopyran-7-yl ester(compound 1g-1e-3) was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-3was used instead of compound 1e-0-5, and that trifluorosulfonicanhydride was used instead of dimethylcarbamoyl chloride.

Compound 1g-1e-3 (200 mg, 0.419 mmol) was added to tetrahydrofuran (6mL), thiophene-3-boronic acid (160 mg, 1.25 mmol),tetrakis(triphenylphosphine)palladium (72 mg, 0.084 mmol) and K₃PO₄ (412mg, 2.51 mmol), and the mixture was stirred at 80° C. for 12 hours. Itwas then purified by silica gel chromatography (hexane:ethylacetate=4:1) to yield the title compound (121 mg).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.10 (1H, s), 8.08(1H, d, J=6.49 Hz), 7.73 (1H, s), 7.65 (1H, d, J=8.01 Hz), 7.59 (1H, dd,J=3.05, 1.53 Hz), 7.50-7.42 (3H, m), 7.36 (1H, dd, J=5.34, 1.53 Hz),4.17 (2H, s), 2.51 (3H, s).

Compound 1g-12-14-Methyl-3-(3-nitrobenzyl)-7-(pyridin-4-yl)-2-oxo-2H-1-benzopyran

The compound trifluorosulfonic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-6-chloro-1-benzopyran-7-yl ester(compound 1g-1e-1) was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-1was used instead of compound 1e-0-5, and that trifluoroacetic anhydridewas used instead of dimethylcarbamoyl chloride.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound 1g-1e-1was used instead of compound 1g-1e-3, and that pyridine-4-boronic acidwas used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.73 (2H, d, J=6.49Hz), 8.10 (1H, s), 8.08 (1H, d, J=9.16 Hz), 7.78 (1H, d, J=9.16 Hz),7.71-7.44 (6H, m), 4.19 (2H, s), 2.56 (3H, s).

Compound 1g-13-14-Methyl-3-(3-nitrobenzyl)-7-(dibenzhydrylidene-amino)-2-oxo-2H-1-benzopyran

Compound 1g-1e-1 (88 mg, 0.2 mmol), BINAP (11 mg, 0.02 mmol),palladium(II) acetate (3 mg, 0.013 mmol), cesium carbonate (164 mg, 0.5mmol) and benzophenoneimine (154 mg, 0.24 mmol) were mixed, and themixture was heated under reflux under nitrogen atmosphere for 3.5 hours.It was then purified by silica gel chromatography (ethylacetate:hexane=8:1 to 4:1) to yield the title compound (49 mg, 52%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.08 (1H, d, J=1.91Hz), 8.06 (1H, d, J=9.54 Hz), 7.76 (2H, d, J=7.25 Hz), 7.64 (1H, d,J=7.63 Hz), 7.55-7.41 (5H, m), 7.29 (3H, m), 7.13 (2H, d, J=4.96 Hz),6.70 (1H, dd, J=8.39, 2.29 Hz), 6.67 (1H, d, J=1.91 Hz), 4.10 (2H, s),2.42 (3H, s).

Compound 1g-14-14-Methyl-3-(3-nitrobenzyl)-7-amino-2-oxo-2H-1-benzopyran

2.5 mL of 2N hydrochloric acid was added to a mixture of compound1g-13-1 (6.2 g) in THF (50 mL), and the obtained mixture was stirred atroom temperature for 20 minutes. A 1N sodium hydroxide aqueous solutionwas further added, and extraction was performed with methylene chloride.After distilling away the solvent, a product (3.9 g, 96%) was obtainedby solidification using a mixture of hexane and ethyl acetate (2:1).

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 8.05 (1H, s), 8.04(1H, d, J=6.49 Hz), 7.68 (1H, d, J=7.63 Hz), 7.56 (1H, t, J=7.63 Hz),7.47 (1H, d, J=8.78 Hz), 6.58 (1H, d, J=8.39 Hz), 6.42 (1H, s), 6.06(2H, s), 4.02 (2H, s), 2.36 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 311.35 (M+1).

Compound 1g-15-1 4-Methyl-3-(3-nitrobenzyl)-7-iodo-2-oxo-2H-1-benzopyran

To a mixture of compound 1g-14-1 (620 mg, 0.064 mmol), 0.013 mL ofconcentrated sulfuric acid and 0.13 mL of water, there was added anaqueous solution (0.013 mL) of NaNO₂(4.6 mg, 0.068 mmol) at 0° C. over aperiod of 1 hour. An aqueous solution (0.09 mL) of potassium iodide (32mg, 0.192 mmol) was then added dropwise at 0° C. over a period of 30minutes, and the mixture was stirred at room temperature for 1 hour. Itwas then purified by silica gel chromatography (hexane:ethylacetate=2:1) to yield the title compound (25 mg, 92%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.08 (1H, s), 8.07(1H, d, J=6.49 Hz), 7.72 (1H, d, J=0.53 Hz), 7.65 (2H, dd, J=8.39, 1.91Hz), 7.46 (1H, t, J=7.63 Hz), 7.35 (1H, d, J=8.39 Hz), 4.14 (2H, s),2.48 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 420.43 (M−1).

5-Tributylstannylthiazole

A hexane solution of n-BuLi (4.14 mL, 10 mmol) was added dropwise to ananhydrous tetrahydrofuran solution of 5-bromothiazole (0.46 mL, 5.0mmol) at −78° C. under nitrogen atmosphere over a period of 30 minutes,and the mixture was stirred for 1 hour. A solution of n-Bu₃SnCl (1.41mL, 5.0 mmol) in THF was then added dropwise over a period of 30 minutesat −78° C., and after stirring for 2 hours, the mixture was raised toroom temperature and stirred for another hour. Three drops of a 1N HClsolution were added, and the organic layer was extracted from theaqueous layer twice with 10 mL of ether. The solvent was distilled awayto yield the title compound (650 mg, 35 mL).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 9.09 (1H, s), 7.88(1H, s), 1.61-0.87(27H, m).

MS (Micromass, Quattromicro, ESI+) m/z: 376.07 (M+1).

Compound 1g-16-14-Methyl-3-(3-nitrobenzyl)-7-(thiazol-5-yl-2-oxo-2H-1-benzopyran

Compound 1g-15-1 (150 mg, 0.36 mmol), 5-tributylstannylthiazole (173 mg,0.46 mmol), bis(triphenylphosphine)palladium dichloride (6.5 mg, 0.009mmol), tri(2-furyl)phosphine (4.3 mg, 0.02 mmol) and acetonitrile (4.5mL) were mixed, and the mixture was heated under reflux under argonatmosphere overnight. It was then purified by silica gel chromatography(hexane:ethyl acetate=2:1; methylene chloride:hexane:ethylacetate=1:1:1) to yield the title compound (126 mg, 70%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.84 (1H, s), 8.20(1H, s), 8.10 (1H, s), 8.09 (1H, d, J=8.39 Hz), 7.68 (2H, t, J=6.87 Hz),7.54 (2H, m), 7.47 (1H, t, J=7.63 Hz), 4.17 (2H, s), 2.53 Hz (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 397.04 (M+1).

2-Tributylstannylthiazole

To a mixture of 2-bromothiazole (4.6 mL, 50 mmol) and anhydrous ether(50 mL), there was added an n-BuLi hexane solution (22 mL, 55 mmol)dropwise at −70° C. under nitrogen atmosphere, and the mixture wasstirred for 30 minutes. A solution of n-Bu₃SnCl (14 mL, 50 mmol) inether (20 mL) was then added at −70° C., and after stirring for 4 hours,the mixture was raised to room temperature and stirred for another hour.After adding water (50 mL), the organic layer was extracted three timeswith ether (50 mL), and the solvent was distilled away. It was thenpurified by silica gel chromatography (hexane:ethyl acetate=20:1) toyield the title compound (17 g, 90%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.17 (1H, d, J=3.05Hz), 7.54 (1H, d, J=3.05 Hz), 1.65-1.55 (6H, m), 1.38-1.19(12H, m), 0.89(9H, t, J=7.25 Hz).

Compound 1g-17-14-Methyl-3-(3-nitrobenzyl)-7-(thiazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-16-1, except that2-tributylstannylthiazole was used instead of 5-tributylstannylthiazole.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.12 (1H, s), 8.08(1H, d, J=8.01 Hz), 7.94 (3H, m), 7.72 (1H, d, J=8.01 Hz), 7.67 (1H, d,J=7.63 Hz), 7.48 (1H, d, J=8.01 Hz), 7.44 (1H, d, J=3.43 Hz), 4.18 (2H,s), 2.54 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 397.04 (M+1).

Compound 1g-18-14-Methyl-3-(3-nitrobenzyl)-7-(pyridin-3-yl)-2-oxo-2H-1-benzopyran

The compound trifluorosulfonic acid2-oxo-2H-3-(3-nitrobenzyl)-4-methyl-1-benzopyran-7-yl ester (compound1g-1e-1) was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-1was used instead of compound 1e-0-5, and that trifluorosulfonicanhydride was used instead of dimethylcarbamoyl chloride.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound 1g-1e-1was used instead of compound 1g-1e-3, and that pyridine-3-boronic acidwas used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.91 (1H, d, J=1.91Hz), 8.67 (1H, dd, J=4.58, 1.53 Hz), 8.11 (1H, s), 8.08 (1H, dd, J=8.77,1.91 Hz), 7.92 (1H, dt, J=8.01, 2.29 Hz), 7.78-7.42 (6H, m), 4.19 (2H,s), 2.56 (3H, s).

Compound 1g-19-34-Methyl-3-(3-nitrobenzyl)-6-chloro-7-(3-methoxyphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that 3-phenoxyboronicacid was used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.09 (1H, s), 8.08(1H, d, J=6.49 Hz), 7.74 (1H, s), 7.65 (1H, d, J=7.63 Hz), 7.49 (1H, t,J=8.01 Hz), 7.39 (1H, t, J=8.77 Hz), 7.35 (1H, s), 7.03 (1H, dd, J=7.63,1.14 Hz), 6.99-6.97 (2H, m), 4.18 (2H, s), 3.86 (3H, s), 2.52 (3H, s).

1-Methyl-2-tributylstannyl-1H-imidazole

n-BuLi (7.6 mL, 18.9 mmol) was added dropwise at −10° C. under nitrogenatmosphere over a period of 30 minutes to an anhydrous tetrahydrofuransolution (20 mL) of 1-methyl-1H-imidazole (1.6 mL, 18.8 mmol), and themixture was stirred for 2.5 hours. Next, a tetrahydrofuran solution (12mL) of Bu₃SnCl (5.1 mL, 18.8 mmol) was added dropwise over a period ofone hour at −78° C., and then the mixture was raised to room temperatureand stirred overnight. The title compound (5.48 g, 79%) was obtained byvacuum distillation (140-142° C., 0.5 mmHg).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.20 (1H, s), 7.01(1H, s), 3.68 (3H, s), 1.56 (6H, m), 1.37-1.15(12H, m), 0.88 (9H, t,J=7.2 Hz).

Compound 1g-20-14-Methyl-3-(3-nitrobenzyl)-7-(1-methyl-1H-imidazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-16-1, except that1-methyl-2-tributylstannyl-1H-imidazole was used instead of5-tributylstannylthiazole.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.10 (1H, s), 8.08(1H, d, J=8.01 Hz), 7.74 (2H, s), 7.67 (1H, d, J=7.25 Hz), 7.58 (1H, s),7.47 (1H, t, J=7.63 Hz), 7.18 (1H, d, J=1.14 Hz), 7.04 (1H, d, J=0.76Hz), 4.19 (2H, s), 3.85 (3H, s), 2.55 (3H, s).

Compound 1g-21-34-Methyl-3-(3-nitrobenzyl)-6-chloro-7-(5-acetylthiophen-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that5-acetylthiophene-2-boronic acid was used instead of thiophene-3-boronicacid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.15-8.05 (3H, m),8.02 (1H, d, J=4.19 Hz), 7.83 (1H, s), 7.72 (2H, dd,), 7.60 (1H, t),4.16 (2H, s), 2.60 (3H, s), 2.54 (3H, s).

Compound 1g-22-14-Methyl-3-(3-nitrobenzyl)-7-(3-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound 1g-1e-1was used instead of compound 1g-1e-3, and that 3-acetylphenylboronicacid was used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.23 (1H, t), 8.05(2H, m), 7.88 (1H, d, J=7.63 Hz), 7.82 (1H, d, J=7.63 Hz), 7.75 (1H,d=1.49 Hz), 7.73 (1H, d, J=8.01 Hz), 7.61 (3H, m), 7.45 (1H, t), 4.22(2H, s), 2.65 (3H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 414.08 (M+1).

Compound 1g-23-14-Methyl-3-(3-nitrobenzyl)-7-(4-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound 1g-1e-1was used instead of compound 1g-1e-3, and that 4-acetylphenylboronicacid was used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.01 (4H, m), 7.85(1H, d, J=8.77 Hz), 7.64 (4H, m), 7.45 (1H, t), 6.85 (1H, d, J=8.39 Hz),4.22 (2H, s), 2.65 (3H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 414.08 (M+1).

Compound 1g-28-14-Methyl-3-(3-nitrobenzyl)-7-(4-N,N-dimethylaminophenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound 1g-1e-1was used instead of compound 1g-1e-3, and that4-N,N-dimethylaminophenylboronic acid was used instead ofthiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.11 (2H, t, d,J=8.77 Hz), 7.53 (7H, m), 6.78 (2H, d, J=8.77 Hz), 4.22 (2H, s), 3.10(6H, s), 2.52 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 415.25 (M+1).

1-Methyl-5-tributylstannyl-1H-imidazole

To a dehydrated tetrahydrofuran solution (10 mL) of 1-methylimidazole(1.6 mL, 18.8 mmol), there was added dropwise a mixture of n-BuLi (18mL, 45 mmol) and TMEDA (6.7 mL, 44.6 mmol) at −20° C. under nitrogenatmosphere. After stirring for 30 minutes, the mixture was raised toroom temperature and stirred for another hour. After again cooling to−20° C., a solution of n-Bu₃SnCl (12.5 mL, 46.4 mmol) in tetrahydrofuran(10 mL) was added dropwise thereto, the mixture was raised to roomtemperature and stirred for 17 hours. The reaction was terminated withwater (15 mL), and then extraction was performed twice with ethylacetate (20 mL). The mixture was then purified by silica gelchromatography (ethyl acetate:methanol=96:4) to yield the title compound(2.2 g, 32%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.61 (1H, s), 7.02(1H, s), 3.67 (3H, s), 1.48-1.56 (6H, m), 1.29-1.37 (6H, m), 1.09 (6H,t, J=8.4 Hz), 0.89 (9H, t, J=7.2 Hz).

MS (Micromass, Quattromicro, EST+) m/z: 372.99 (M+2).

Compound 1g-32-14-Methyl-3-(3-nitrobenzyl)-7-(3-methyl-3H-imidazol-4-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-16-1, except that1-methyl-5-tributylstannyl-1H-imidazole was used instead of5-tributylstannylthiazole.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.08 (2H, d, J=6.9Hz), 7.70 (2H, m), 7.58 (1H, s), 7.47 (1H, t, J=7.8 Hz), 7.38 (2H, m),7.26 (1H, d, J=3.9 Hz), 4.18 (2H, s), 3.76 (3H, s), 2.53 (3H, s).

Compound 1h-1-5 Dimethylcarbamic acid2-oxo-2H-3-(2-fluoro-3-aminobenzyl)-4-methyl-6-fluoro-1-benzopyran-7-ylester

Tin(II) chloride dihydrate (923 mg, 4.09 mmol) was added to anethanol/ethyl acetate solution (volume ratio 1:1, 50 mL) of compound1g-1-5 (342.5 mg, 0.819 mmol), and the mixture was stirred at 80° C. for3 hours. Ethyl acetate was added to the reaction solution, and theorganic layer was washed with sodium carbonate solution and saturatedsaline, and dried over anhydrous magnesium sulfate. The solvent wasdistilled away under reduced pressure to yield the title compound (311.3mg, 98%) as a white solid.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.41 (3H, s), 2.95 (3H, s), 3.09 (3H,s), 4.08 (2H, s), 6.21-6.26 (1H, m), 6.58-6.75 (2H, m), 7.47 (1H, d,J=6.8 Hz), 7.83 (1H, d, J=11.2 Hz).

ESI (LC/MS positive mode) m/z: 389 (M+H).

Compound 1h-1-1 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-1was used instead of compound 1g-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.42 (3H, s), 3.03 (3H, s), 3.13 (3H,s), 3.60 (2H, brs), 3.97 (2H, s), 6.51 (1H, dd, J=2.0, 7.7 Hz), 6.58(1H, s), 6.64 (1H, d, J=7.7 Hz), 7.02-7.12 (3H, m), 7.59 (1H, d, J=8.9Hz).

ESI (LC/MS positive mode) m/z: 352 (M+H).

Compound 1h-1-2 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-6-fluoro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-2was used instead of compound 1g-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.44 (3H, s), 3.02 (3H, s), 3.15 (3H,s), 3.95 (2H, s), 6.54-6.60 (2H, m), 7.00 (1H, dd, J=7.6, 7.6 Hz), 7.29(1H, d, J=6.6 Hz), 7.64 (1H, d, J=11.1 Hz).

ESI (LC/MS positive mode) m/z: 371 (M+H).

Compound 1h-1-3 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-6-chloro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-3was used instead of compound 1g-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.40 (3H, s), 3.04 (3H, s), 3.15 (3H,s), 3.96 (2H, s), 6.45-6.65 (3H, m), 7.05 (1H, dd, J=7.7 Hz), 7.25 (1H,s), 7.64 (1H, s).

ESI (LC/MS positive mode) m/z: 387 (M+H).

Compound 1h-1-4 Dimethylcarbamic acid2-oxo-2H-3-(2-fluoro-3-aminobenzyl)-4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-4was used instead of compound 1g-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.06 (3H, s), 3.91 (2H,s), 5.07 (2H, brs), 6.22 (1H, brt, J=7.3 Hz), 6.55-6.75 (2H, m), 7.17(1H, dd, J=8.7, 2.3 Hz), 7.24 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.7 Hz).

ESI (LC/MS positive mode) m/z: 371 (M+1H).

Compound 1h-1-7 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-6-iodo-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-7was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.43 (3H, s), 2.96 (3H, s), 3.13 (3H,s), 3.83 (2H, s), 4.96 (2H, brs), 6.35-6.38 (3H, m), 6.89 (1H, dd,J=7.8, 7.8 Hz), 7.37 (1H, s), 8.22 (1H, s).

ESI (LC/MS positive mode) m/z: 479 (M+H).

Compound 1h-1-8 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-6-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-8was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.22 (3H, s), 2.43 (3H, s), 2.94 (3H,s), 3.10 (3H, s), 3.83 (2H, s), 4.96 (2H, brs), 6.35-6.38 (3H, m), 6.90(1H, dd, J=8.1, 8.1 Hz), 7.21 (1H, s), 7.73 (1H, s).

ESI (LC/MS positive mode) m/z: 367 (M+H).

Compound 1h-1-9 Dimethylcarbamic acid2-oxo-2H-3-(3-aminobenzyl)-4-methyl-6-cyano-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-9was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.46 (3H, s), 2.97 (3H, s), 3.12 (3H,s), 3.84 (2H, s), 4.96 (2H, brs), 6.36-6.38 (3H, m), 6.90 (1H, dd,J=7.9, 7.9 Hz), 7.59 (1H, s), 8.44 (1H, s).

ESI (LC/MS positive mode) m/z: 378 (M+H).

Compound 1h-1-10 Dimethylcarbamic acid2-oxo-2H-3-(2-aminopyridin-4-ylmethyl)-4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-10was used instead of compound 1e-0-5.

¹H NMR (300 MHz) (DMSO-d₆) δ (ppm): 2.42 (3H, s), 2.93 (3H, s), 3.06(3H, s), 3.82 (2H, s), 5.75 (2H, brs), 6.19 (1H, s), 6.37 (1H, dd,J=1.52, 5.34 Hz), 7.18 (1H, dd, J=2.28, 8.77 Hz), 7.25 (1H, d, J=2.28Hz), 7.76 (1H, d, J=5.34 Hz), 7.84 (1H, d, J=8.77 Hz).

Compound 1h-1-11 Dimethylcarbamic acid2-oxo-2H-3-(2-aminopyridin-4-ylmethyl)-4-methyl-6-fluoro-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-11was used instead of compound 1e-0-5.

¹H NMR (300 MHz) (DMSO-d₆) δ (ppm): 2.41 (3H, s), 2.94 (3H, s), 3.08(3H, s), 3.82 (2H, s), 5.75 (2H, brs), 6.19 (1H, s), 6.37 (1H, d, J=4.95Hz), 7.48 (1H, d, J=7.24 Hz), 7.76 (1H, d, J=5.72 Hz), 7.85 (1H, d,J=9.53 Hz).

Compound 1h-1-13 Dimethylcarbamic acid3-(6-aminopyridin-2-ylmethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-13was used instead of compound 1e-0-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.93 (3H, s), 3.07 (2H,d), 3.88 (2H, s), 5.79 (2H, brs), 6.23 (1H, d, J=8.1 Hz), 6.30 (1H, d,J=8.1 Hz), 7.15-7.26 (3H, m), 7.83 (1H, d, J=10.8 Hz).

ESI (LC/MS positive mode) m/z: 354 (M+H).

Compound 1h-1-14 Dimethylcarbamic acid3-(6-aminopyridin-2-ylmethyl)-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-14was used instead of compound 1e-0-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.45 (3H, s), 3.04 (3H, s), 3.09 (3H,s), 4.04 (2H, s), 6.31 (1H, d, J=7.8 Hz), 6.54 (1H, d, J=7.8 Hz),7.15-7.40 (3H, m).

ESI (LC/MS positive mode) m/z: 372 (M+H).

Compound 1h-1-15 Dimethylcarbamic acid3-(6-aminopyridin-2-ylmethyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-15was used instead of compound 1e-0-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 3.05 (3H, s), 3.17 (3H,s), 4.04 (2H, s), 6.31 (1H, d, J=7.8 Hz), 6.55 (1H, d, J=7.8 Hz),7.20-7.35 (2H, m), 7.66 (1H, s).

ESI (LC/MS positive mode) m/z: 388 (M+H).

Compound 1h-1-4F Dimethylcarbamic acid3-(3-amino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

Ethyl acetate (2.0 mL) was added to dimethylcarbamic acid4-fluoromethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester (20.5 mg) (6c-1-4), and tin(II) chloride dihydrate (60 mg) wasadded to the resultant suspension while stirring at room temperature.The suspension was heated under reflux for 1.5 hours, and after coolingto room temperature, saturated sodium hydrogen carbonate was added, andthe mixture was extracted with ethyl acetate. The resultant organiclayer extraction liquid was washed with saturated saline, and theorganic layer was dried over anhydrous magnesium sulfate. The solventwas then distilled away under reduced pressure to yield the titlecompound (19.5 mg).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.03 (3H, s), 3.13 (3H, s), 4.09 (2H,s), 5.66 (2H, d, J=46.8 Hz), 6.62 (1H, brt, 7.9 Hz), 6.65 (1H, td,J=7.9, 1.0 Hz), 6.83 (1H, dd, J=7.9, 1.0 Hz), 7.12 (1H, dd, J=8.2, 2.3Hz), 7.15 (1H, d, J=2.3 Hz), 7.76 (1H, dd, J=8.2, 2.3 Hz).

ESI (LC/MS positive mode) m/z: 389 (M+H).

Compound 1h-1-1F Dimethylcarbamic acid3-(3-aminobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-4F, except that compound 6c-1-1was used instead of compound 6c-1-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.07 (3H, s), 3.91 (2H,s), 4.98 (2H, brs), 5.81 (2H, d, J=46.3 Hz), 6.29-6.43 (3H, m), 6.91(1H, t, J=8.2 Hz), 7.21 (1H, dd, J=8.7, 2.3 Hz), 7.30 (1H, d, J=2.3 Hz),7.89 (1H, d, J=8.7, 2.3 Hz).

ESI (LC/MS positive mode) m/z: 371 (M+H).

Compound 1h-1-2F Dimethylcarbamic acid3-(3-aminobenzyl)-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-4F, except that compound 6c-1-2was used instead of compound 6c-1-4.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.04 (3H, s), 3.15 (3H, s), 4.03 (2H,brs), 5.59 (2H, d, J=47.0 Hz), 6.50-6.60 (3H, m), 7.01-7.10 (1H, m),7.20-7.30 (1H, m), 7.54 (2H, 1H, dd, J=10.5, 1.8 Hz).

ESI (LC/MS positive mode) m/z: 389 (M+H).

Compound 1h-1-3F Dimethylcarbamic acid6-chloro-4-fluoromethyl-3-(3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-4F, except that compound 6c-1-3was used instead of compound 6c-1-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.04 (s, 1H), 7.54 (s, 1H), 6.90 (t,J=7.8 Hz, 1H), 6.36 (m, 3H), 5.84 (d, J=46.0 Hz, 2H), 3.92 (s, 2H), 3.11(s, 3H), 2.95 (s, 3H).

ESIMS m/z: 405 (M+H).

Compound 1h-1-38 Dimethylcarbamic acid3-(3-aminobenzyl)-6-carbamoyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-38was used instead of compound 1g-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 2.90 (3H, s), 3.05 (3H,s), 3.85 (2H, s), 4.97 (2H, s), 6.35-6.38 (3H, m), 6.90 (1H, t, J=7.8Hz), 7.28 (1H, s), 7.50 (1H, s), 7.80 (1H, s), 7.98 (1H, s).

ESI (LC/MS positive mode) m/z: 396 (M+H).

Compound 1h-1-39 Dimethylcarbamic acid3-(3-aminobenzyl)-4-methyl-2-oxo-6-trimethylsilanylethynyl-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-39was used instead of compound 1g-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.23 (9H, s), 2.44 (3H, s), 2.94 (3H,s), 3.11 (3H, s), 3.82 (2H, s), 4.96 (2H, s), 6.12-6.15 (3H, m), 6.66(1H, t, J=8.1 Hz), 7.14 (1H, s), 7.68 (1H, s).

ESI (LC/MS positive mode) m/z: 449 (M+H).

Compound 1h-1-40 Dimethylcarbamic acid3-(3-aminobenzyl)-6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

TBAF (1.0 M in 0.245 mL of THF) was added to a solution of compound1g-1-39 (100 mg, 0.223 mmol) in THF (2 mL), and the mixture was stirredat room temperature for 1 hour. The reaction mixture was thenconcentrated under reduced pressure to yield a crude product, which wasthen purified by column chromatography to yield the title compound (77mg, 92%).

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 3.83 (2H, s), 4.45 (1H, s), 4.97 (1H, brs), 6.35-6.38 (3H, m), 6.96(1H, t, J=8.0 Hz), 7.38 (1H, s), 7.97 (1H, s).

ESI (LC/MS positive mode) m/z: 377 (M+H).

Compound 1h-1-59 Dimethylcarbamic acid3-(2-aminobenzoylamino)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-59was used instead of compound 1g-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.63 (s, 1H), 7.86 (d, 1H, J=8.7 Hz),7.76 (d, 1H, J=6.6 Hz), 7.31 (d, 1H, J=2.3 Hz), 7.25-7.20 (m, 2H), 6.75(d, 1H. J=8.2 Hz), 6.58 (t, 1H, J=7.3 Hz), 6.50 (s, 2H), 3.08 (s, 3H),2.94 (s, 3H), 2.36 (s, 3H).

ESIMS m/z: 382 (M+H).

Compound 1h-1d-1 Pyrrolidine-1-carboxylic acid3-(3-aminobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1d-1was used instead of compound 1g-1-5.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 1.90-2.04 (4H, m), 2.42 (3H, s), 3.50(2H, t, J=6.6 Hz), 3.56-3.61 (4H, m), 3.97 (2H, s), 6.49-6.66 (3H, m),7.05 (1H, t, J=7.8 Hz), 7.09-7.17 (2H, m), 7.59 (1H, d, J=7.4 Hz).

ESI (LC/MS positive mode) m/z: 379 (M+H).

Compound 1h-2-14-Methyl-3-(3-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-2-1was used instead of compound 1g-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.45 (3H, s), 3.60 (1H, brs), 3.99 (2H,s), 6.52 (1H, dd, J=2.0, 7.6 Hz), 6.57 (1H, s), 6.64 (1H, d, J=7.6 Hz),7.06 (1H, dd, J=7.6, 7.6 Hz), 7.11 (1H, t, J=4.8 Hz), 7.16 (1H, dd,J=2.3, 8.7 Hz), 7.23 (1H, d, J=2.3 Hz), 7.68 (1H, d, J=8.7 Hz), 8.59(2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 360 (M+H).

Compound 1h-2-34-Methyl-3-(3-aminobenzyl)-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-2-3was used instead of compound 1g-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.42 (3H, s), 4.00 (2H, s), 6.52 (1H,d, J=7.7 Hz), 6.55 (1H, brs), 6.63 (1H, d, J=7.7 Hz), 7.04 (1H, t, J=7.7Hz), 7.10 (1H, t, J=4.8 Hz), 7.26 (1H, s), 7.72 (1H, s), 8.60 (2H, d,J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 394 (M+H).

Compound 1h-2-44-Methyl-3-(2-fluoro-3-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

(Synthesis Scheme 1)

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-2-4was used instead of compound 1g-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.45 (3H, s), 3.93 (2H, s), 5.08 (2H,br.s), 6.25 (1H, ddd, J=7.2, 1.7 Hz, J_(HF)=7.2 Hz), 6.61 (1H, ddd,J=8.2, 1.7 Hz, J_(HF)=8.2 Hz), 6.73 (1H, dd, J=8.2, 7.2 Hz), 7.26 (1H,dd, J=8.8, 2.4 Hz), 7.34 (1H, t, J=4.8 Hz), 7.37 (1H, d, J=2.4 Hz), 7.89(1H, d, J=8.8 Hz), 8.68 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 378 (M+H).

Compound 1h-2-4S23-{2-Fluoro-3-aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzothiopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-4S2 was used instead of compound 4a-0-4.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 4.02 (2H, s), 5.09 (2H, s), 6.11 (1H,dd, J=7.0 Hz, J_(HF)=7.0 Hz), 6.60 (1H, dd, J=8.5 Hz, J_(HF)=8.5 Hz),6.71 (1H, dd, J=7.7, 7.7 Hz), 7.28 (1H, dd, J=8.9,2.3 Hz), 7.31-7.42(2H, m), 7.61-7.64 (1H, m), 8.67-8.71 (2H, m).

The CH₃ peak was overlapped with the DMSO peak.

ESI (LC-MS positive mode) m/z: 394 (M+H).

Compound 1h-2-52-Oxo-2H-3-(2-fluoro-3-aminobenzyl)-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 4a-0-5was used instead of compound 1e-0-4.

¹H-NMR (CD₃OD, 270 MHz) δ (ppm): 2.39 (3H, s), 4.03 (2H, s), 6.29-6.43(1H, m), 6.69-6.78 (2H, m), 7.28-7.39 (3H, m), 7.68-7.72 (1H, m), 7.98(1H, m).

ESI (LC/MS positive mode) m/z: 396 (M+H).

Compound 1h-2-64-Methyl-3-(2-methyl-3-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 4a-0-6 was used instead of compound 4a-0-4.

¹H NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.61 (2H, d, J=5.0 Hz), 7.70(1H, d, J=8.8 Hz), 7.26 (1H, d, J=3.1 Hz), 7.18 (1H, dd, J=2.7, 8.8 Hz),7.12 (1H, t, J=4.8 Hz), 6.88 (1H, t, J=7.8 Hz), 6.59 (1H, d, J=7.6 Hz),6.32 (1H, d, J=7.6 Hz), 4.02 (2H, s), 3.73-3.63 (2H, br), 2.35 (3H, s),2.22 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 373.97 (M+H).

Compound 1h-2-104-Methyl-3-(2-aminopyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 5d-0-10was used instead of compound 1e-0-4.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.36 (3H, s), 3.85 (2H, s), 6.32 (1H,brs), 6.42 (1H, d, J=5.7 Hz), 7.10-7.20 (3H, m), 7.66 (1H, d, J=4.9 Hz),7.75 (1H, d, J=8.6 Hz), 8.52 (2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 361 (M+H).

Compound 1h-2-124-Methyl-3-(2-aminopyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that compound 5d-0-12was used instead of compound 1e-0-4.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.42 (3H, s), 3.96 (2H, s), 6.35 (1H,brs), 6.53 (1H, d, J=6.5 Hz), 7.13 (1H, dd, J=4.9 Hz), 7.31 (1H, s),7.74 (1H, s), 7.96 (1H, d, J=6.5 Hz), 8.59 (2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 395 (M+H).

Compound 1h-2-4F3-(3-Amino-2-fluorobenzyl)-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 6c-2-4was used instead of compound 1g-1-5.

1H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.68 (d, J=4.9 Hz, 2H), 7.94 (dd,J=8.9, 2.4 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.33 (t, J=4.6 Hz, 1H), 7.29(dd, J=8.7, 2.2 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 6.60 (td, J=8.1, 1.6Hz, 1H), 6.24 (t, J=6.2 Hz, 1H), 5.83 (d, J=46.2 Hz, 2H), 5.08 (s, 2H),4.00 (s, 2H).

ESIMS m/z: 396 (M+H).

Compound 1h-2-163-(3-Fluoro-2-aminopyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.45-2.55 (3H, m), 3.94 (2H, s), 6.12(2H, brs), 6.28 (1H, dd, J=4.7 Hz), 7.27 (1H, dd, J=8.6 Hz, J=2.1 Hz),7.34 (1H, dd, J=4.9 Hz), 7.38 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=4.7 Hz),7.91 (1H, d, J=8.6 Hz), 8.68 (2H, d, J=4.7 Hz).

ESI (LC/MS positive mode) m/z: 479 (M+H).

Compound 1h-2-173-(2-Amino-3-fluoropyridin-4-ylmethyl)-6-fluoro-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-17 was used instead of compound 4a-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.45 (3H, s), 3.94 (2H, s), 6.13 (2H,s), 6.28 (1H, t, J=5.1 Hz), 7.38 (1H, t, J=4.8 Hz), 7.59 (1H, d, J=5.1Hz), 7.65 (1H, d, J=6.8 Hz), 7.92 (1H, d, J=11.5 Hz), 7.91 (1H, d,J=11.5 Hz), 8.70 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 397 (M+H).

Compound 1h-2-193-(3-Fluoro-2-aminopyridin-4-ylmethyl)-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-19 was used instead of compound 4a-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.15 (3H, s), 2.46 (3H, s), 3.93 (2H,s), 6.10 (2H, brs), 6.27 (1H, dd, J=5.1 Hz), 7.31 (1H, t, J=4.7 Hz),7.58 (1H, d, J=5.1 Hz), 7.82 (1H, s), 8.66 (2H, d, J=8.66 Hz).

EST (LC/MS positive mode) m/z: 393 (M+H).

Compound 1h-2-19Me3-(2-Amino-3-fluoropyridin-4-ylmethyl)-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-19Me was used instead of compound 4a-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.06 (3H, brt, J=7.4 Hz), 2.16 (3H,s), 2.89 (2H, brq, J=7.4 Hz), 3.91 (2H, s), 6.12 (2H, s), 6.26 (1H, t,J=5.1 Hz), 7.28-7.37 (3H, m), 7.58 (1H, d, J=5.1 Hz), 7.83 (1H, s), 8.67(2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 407 (M+H).

Compound 1h-2-454-Methyl-3-(2-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 4a-0-45 was used instead of compound 4a-0-4.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.59 (2H, d, J=4.6 Hz), 7.69(1H, d, J=8.8 Hz), 7.24 (1H, d, J=2.3 Hz), 7.18 (1H, dd, J=2.3, 8.8 Hz),7.11 (1H, t, J=4.8 Hz), 7.03 (1H, t, J=7.4 Hz), 6.97 (1H, d, J=7.2 Hz),6.69 (2H, d, J=7.2 Hz), 3.92 (2H, s), 2.49 (3H, s).

Compound 1h-2-464-Methyl-3-(4-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 4a-0-46 was used instead of compound 4a-0-4.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.59 (2H, d, J=5.0 Hz), 7.67(1H, d, J=8.8 Hz), 7.22 (1H, d, J=2.3 Hz), 7.15 (1H, dd, J=2.3, 8.8 Hz),7.10 (1H, t, J=5.0 Hz), 7.05 (2H, d, J=8.4 Hz), 6.61 (2H, d, J=8.4 Hz),5.30 (2H, s), 3.95 (2H, s), 2.45 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 359.99 (M+H).

Compound 1h-2-473-(3-Aminobenzyl)-4-hydroxy-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-2-47was used instead of compound 1g-1-5.

¹H NMR (270 MHz, CD₃OD) δ (ppm): 8.54 (d, 2H, J=4.9 Hz), 7.94 (d, 1H,J=8.4 Hz), 7.32-7.25 (m, 2H), 7.20-7.10 (m, 4H), 7.02 (m, 1H), 3.89 (s,2H).

ESIMS m/z: 362 (M+H).

Compound 1h-2-513-(3-Aminophenylamino)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 4a-0-51 was used instead of compound 4a-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 7.81 (d, 1H,J=8.6 Hz), 7.38 (d, 1H, J=2.1 Hz), 7.33 (t, 1H, J=4.8 Hz), 7.29-7.24 (m,2H), 6.80 (t, 1H, J=7.7 Hz), 6.00 (m, 2H), 5.86 (s, 1H), 4.86 (s, 2H),2.26 (s, 3H).

ESIMS m/z: 361 (M+H).

Compound 1h-2-523-(3-Aminophenoxy)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-52 was used instead of compound 4a-0-4.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 8.61 (1H, d, J=5.0 Hz), 7.68 (1H, d,J=8.4 Hz), 7.28 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=2.3, 8.4 Hz), 7.12(1H, m), 7.06 (1H, m), 6.38 (1H, m), 6.33 (2H, m), 3.69 (2H, s), 2.40(3H, s).

MS (ESI+) m/z: 361.99 (M+H).

Compound 1h-2-533-(3-Aminophenylthioxy)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-53 was used instead of compound 4a-0-4.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 8.61 (2H, d, J=4.6 Hz), 7.75 (1H, d,J=8.8 Hz), 7.26 (1H, m), 7.21 (1H, dd, J=2.3, 8.8 Hz), 7.13 (1H, m),7.04 (1H, m), 6.64 (1H, m), 6.57 (1H, m), 6.50 (1H, m), 3.66 (2H, bs),2.76 (3H, s).

MS (ESI+) m/z: 377.98 (M+H).

Compound 1h-2-743-(2-Aminothiazol-4-ylmethyl)-7-(pyrimidin-2-yloxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5d-0-74 under the sameconditions as in the manufacturing example for compound 1h-2-4(synthesis scheme 2).

¹H-NMR (Bruker (ARX-300), DMSO-d₆) δ (ppm): 8.68 (2H, d, J=4.5 Hz), 7.88(1H, d, J=8.4 Hz), 7.35-7.31 (2H, m), 7.24 (1H, dd, J=9.0, 2.4 Hz), 6.83(2H, s), 6.10 (1H, s), 3.79 (2H, s), 2.47 (3H, s).

Compound 1h-3-14-Methyl-3-(3-aminobenzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-3-1was used instead of compound 1g-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 4.00 (2H, s), 6.50-6.67(3H, m), 6.92 (1H, d, J=3.8 Hz), 7.05 (1H, dd, J=7.8, 7.8 Hz), 7.21-7.33(3H, m), 7.64 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 365 (M+H).

Compound 1h-3-34-Methyl-3-(3-aminobenzyl)-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-3-3was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.45 (3H, s), 3.83 (2H, s), 4.96 (2H,brs), 6.35-6.37 (3H, m), 6.86-6.92 (1H, m), 7.28 (1H, d, J=3.6 Hz), 7.32(1H, d, J=3.6 Hz), 7.73 (1H, s), 8.09 (1H, s).

ESI (LC/MS positive mode) m/z: 399 (M+H).

Compound 1h-3-44-Methyl-3-(2-fluoro-3-aminobenzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

(Synthesis Scheme 1)

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-3-4was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 3.92 (2H, s), 6.24 (1H,ddd, J=1.5, 7.0 Hz, J_(HF)=7.0 Hz), 6.61 (1H, ddd, J=1.5, 8.3 Hz,J_(HF)=8.3 Hz), 6.72 (1H, dd, J=7.0, 8.3 Hz), 7.34-7.38 (4H, m), 7.49(1H, d, J=2.5 Hz), 7.92 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 383 (M+H).

Compound 1h-3-84-Methyl-3-(3-aminobenzyl)-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-3-8was used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.27 (3H, s), 2.45 (3H, s), 3.84 (2H,s), 4.97 (2H, s), 6.33-6.40 (3H, m), 6.90 (1H, dd, J=8.2, 8.2 Hz),7.27-7.31 (2H, m), 7.44 (1H, s), 7.84 (1H, s).

ESI (LC/MS positive mode) m/z: 379 (M+H).

Compound 1h-3-193-(2-Amino-3-fluoropyridin-4-ylmethyl)-4,6-dimethyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-19 was used instead of compound 4a-0-4.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.87 (1H, s), 7.58 (1H, d, J=4.8 Hz),7.45 (1H, s), 7.35-7.25 (2H, m), 6.27 (1H, dd, J=4.8 Hz), 6.10 (2H,brs), 3.93 (2H, s), 2.46 (3H, s), 2.28 (3H, s).

ESI (LC/MS positive mode) m/z: 398 (M+H).

Compound 1h-2a-43-{2-Fluoro-3-aminobenzyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat 2-chloro-5-fluoropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.44 (2H, s), 7.69 (1H, d,J=8.8 Hz), 7.21 (1H, d, J=2.7 Hz), 7.14 (1H, dd, J=2.3, 8.8 Hz), 6.81(1H, m), 6.63 (1H, m), 6.55 (1H, m), 4.06 (2H, s), 3.70 (2H, s), 2.44(3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 395.85 (M+H).

Compound 1h-2b-43-{2-Fluoro-3-aminobenzyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat 2,4-dichloropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.51 (1H, d, J=5.7 Hz), 7.69(1H, d, J=8.8 Hz), 7.18 (1H, d, J=2.7 Hz), 7.13 (1H, dd, J=2.3, 8.8 Hz),6.92 (1H, d, J=5.7 Hz), 6.82 (1H, m), 6.64 (1H, m), 6.57 (1H, m), 4.07(2H, s), 3.71 (2H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 411.75 (M), 413.80 (M+2).

Compound 1h-5-43-{2-Fluoro-3-aminobenzyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat 6-chloro-2,4-dimethoxypyrimidine was used instead of2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.64 (1H, d, J=8.8 Hz), 7.15(1H, d, J=2.7 Hz), 7.09 (1H, dd, J=2.3, 8.8 Hz), 6.81 (1H, m), 6.64 (1H,m), 6.57 (1H, m), 5.86 (1H, s), 4.05 (2H, s), 3.97 (3H, s), 3.89 (3H,s), 3.70 (2H, brs), 2.44 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 438.06 (M+H).

Compound 1h-3a-43-(2-Fluoro-3-aminobenzyl)-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-3-4 (synthesis scheme 2), exceptthat 2-chlorobenzothiazole was used instead of 2-bromothiazole.

¹H NMR (Bruker, 300 MHz) CDCl₃ δ (ppm): 7.72 (3H, m), 7.47 (1H, d, J=2.7Hz), 7.42 (1H, m), 7.32 (2H, m), 6.82 (1H, m), 6.64 (1H, m), 6.57 (1H,m), 4.07 (2H, s), 3.70 (2H, s), 2.45 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 433.00 (M+H).

Compound 1h-1a-4 Dimethylthiocarbamic acid4-methyl-3-(2-fluoro-3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-3-4 (synthesis scheme 2), exceptthat dimethylthiocarbamoyl chloride was used instead of 2-bromothiazole.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.64 (1H, d, J=9.5 Hz), 7.06(1H, s), 7.04 (1H, dd, J=2.3, 8.0 Hz), 6.81 (1H, m), 6.63 (1H, m), 6.55(1H, m), 4.05 (2H, s), 3.70 (2H, s), 3.47 (3H, s), 3.38 (3H, s), 2.43(3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 387.04 (M+H).

Compound 1h-3b-43-(2-Fluoro-3-aminobenzyl)-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-3-4 (synthesis scheme 2), exceptthat 2,5-dibromothiazole was used instead of 2-bromothiazole.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.66 (1H, d, J=8.8 Hz), 7.29(1H, d, J=2.7 Hz), 7.21 (1H, dd, J=2.7, 9.7 Hz), 7.19 (1H, s), 6.81 (1H,m), 6.63 (1H, m), 6.55 (1H, m), 4.05 (2H, s), 3.70 (2H, s), 2.43 (3H,s).

MS (Micromass, Quattromicro, ESI+) m/z: 460.67 (M), 462.75 (M+2).

Compound 1h-2a-164-Methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2-chloro-5-fluoropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.44 (2H, s), 7.71 (1H, d,J=5.3 Hz), 7.69 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=1.9 Hz), 7.16 (1H, dd,J=1.9, 8.4 Hz), 6.50 (1H, m), 4.55 (2H, brs), 4.05 (2H, s), 2.43 (3H,s).

MS (Micromass, Quattromicro, ESI+) m/z: 396.98 (M+H).

Compound 1h-2b-164-Methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2,4-dichloropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.52 (1H, d, J=5.3 Hz), 7.73(1H, d, J=1.9 Hz), 7.71 (1H, d, J=5.3 Hz), 7.21 (1H, d, J=2.7 Hz), 7.15(1H, dd, J=1.9, 8.4 Hz), 6.93 (1H, d, J=5.7 Hz), 6.53 (1H, m), 4.57 (2H,brs), 4.06 (2H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 412.98 (M), 414.95 (M+2).

Compound 1h-5-164-Methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2,4-dimethoxy-6-chloropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.72 (1H, d, J=5.3 Hz), 7.65(1H, d, J=8.8 Hz), 7.17 (1H, d, J=2.3 Hz), 7.12 (1H, dd, J=2.3, 8.8 Hz),6.52 (1H, m), 5.87 (1H, s), 4.57 (2H, brs), 4.04 (2H, s), 3.98 (3H, s),3.89 (3H, s), 2.44 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 439.02 (M+H).

Compound 1h-3a-164-Methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2-chlorobenzothiazole was used instead of 2-bromopyrimidine.

¹H NMR (Bruker, 300 MHz) CDCl₃ δ (ppm): 7.73 (4H, m), 7.50 (1H, d, J=2.3Hz), 7.43 (1H, m), 7.36 (1H, dd, J=2.7, 8.8 Hz), 7.33 (1H, m), 6.51 (1H,m), 4.58 (2H, bs), 4.05 (2H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 433.96 (M+H).

Compound 1h-3b-164-Methyl-3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2,5-dibromothiazole was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.71 (1H, d, J=5.3 Hz), 7.68(1H, d, J=8.8 Hz), 7.31 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=2.7, 8.8 Hz),7.20 (1H, s), 6.50 (1H, m), 4.56 (2H, s), 4.04 (2H, s), 2.44 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 461.90 (M), 463.90 (M+2).

Compound 1h-1a-16 Dimethylthiocarbamic acid2-oxo-2H-3-(2-amino-3-fluoropyridin-4-ylmethyl)-4-methyl-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and thatdimethylthiocarbamoyl chloride was used instead of 2-bromopyrimidine.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.71 (1H, d, J=5.3 Hz), 7.65(1H, d, J=9.2 Hz), 7.08 (1H, s), 7.06 (1H, d, J=4.6 Hz), 6.50 (1H, m),4.55 (2H, brs), 4.04 (2H, s), 3.47 (3H, s), 3.38 (3H, s), 2.43 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 388.00 (M+H).

Compound 1h-1b-13-(3-Aminobenzyl)-7-isobutoxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1b-1was used instead of compound 1g-1-5.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 0.98 (3H, s), 1.00 (3H, s), 1.95-2.12(1H, m), 2.39 (3H, s), 3.79 (2H, s), 3.86 (2H, d, J=6.5 Hz), 4.96 (2H,br.s), 6.32-6.41 (3H, m), 6.82-7.00 (3H, m), 7.72 (1H, d, J=9.5 Hz).

ESI (LC-MS positive mode) m/z: 338 (M+H).

Compound 1h-1c-13-(3-Aminobenzyl)-7-(2-fluoroethoxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1c-1was used instead of compound 1g-1-5.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.40 (3H, s), 3.80 (2H, s), 4.27-4.32(1H, m), 4.37-4.45 (1H, m), 4.66-4.71 (1H, m), 4.84-4.89 (1H, m), 4.96(2H, br.s), 6.32-6.39 (3H, m), 6.90 (1H, dd, J=8.6, 7.3 Hz), 6.96-7.07(2H, m), 7.75 (1H, d, J=8.6 Hz).

ESI (LC-MS positive mode) m/z: 328 (M+H).

Compound 1h-1c-33-(3-Aminobenzyl)-6-chloro-7-(2-fluoroethoxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1c-3was used instead of compound 1g-1-5.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.41 (3H, s), 3.80 (2H, s), 4.36-4.43(1H, m), 4.46-4.54 (1H, m), 4.68-4.75 (1H, m), 4.86-4.93 (1H, m), 4.96(2H, br.s), 6.32-6.39 (3H, m), 6.90 (1H, dd, J=8.6, 7.0 Hz), 7.29 (1H,s), 7.90 (1H, s).

ESI (LC-MS positive mode) m/z: 362 (M+H).

Compound 1h-11-34-Methyl-3-(3-aminobenzyl)-7-(thiophen-3-yl)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-11-3was used instead of compound 1g-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.68 (1H, s),7.57((1H, dd, J=3.05, 1.14 Hz), 7.34-7.39 (2H, m), 7.35 (1H, dd, J=3.82,1.14 Hz), 7.06 (1H, t, J=8.01 Hz), 6.64 (1H, d, J=8.01 Hz), 6.60 (1H,s), 6.53 (1H, dd, J=7.63, 1.53 Hz), 3.99 (2H, s), 2.44 (3H, s), 2.27(2H, br).

Compound 1h-12-14-Methyl-3-(3-aminobenzyl)-7-(pyridin-4-yl)-2-oxo-2H-1-benzopyran

2 mL of a mixture of MeOH and H₂O (9:1), metallic zinc (81 mg, 1.2 mmol)and ammonium chloride (20 mg, 1.6 mmol) were added to compound 1g-12-1(23 mg, 0.062 mmol), and the obtained mixture was stirred at roomtemperature for two days. It was then purified by silica gelchromatography (methylene chloride:methanol=30:1) to yield the titlecompound (15 mg, 73%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.72 (2H, d, J=6.10Hz), 7.73 (1H, d, J=8.01 Hz), 7.59-7.53 (4H, m), 7.06 (1H, t, J=7.63Hz), 6.66 (1H, d, J=7.63 Hz), 6.62 (1H, s), 6.53 (1H, dd, J=7.63, 2.29Hz), 4.01 (2H, s), 2.49 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 343.40 (M+1).

Compound 1h-16-14-Methyl-3-(3-aminobenzyl)-7-(thiazol-5-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-16-1was used instead of compound 1g-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.82 (1H, s), 8.18(1H, s), 7.64 (1H, d, J=8.01 Hz), 7.52 (1H, s), 7.50 (1H, d, J=8.39 Hz),7.09 (1H, t, J=7.63 Hz), 6.66 (1H, d, J=7.63 Hz), 6.62 (1H, s), 6.53(1H, d, J=7.63 Hz), 3.99 (2H, s), 2.46 (3H, s).

Compound 1h-17-14-Methyl-3-(3-aminobenzyl)-7-(thiazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-17-1was used instead of compound 1g-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 8.02 (1H, d, J=3.05Hz), 7.94 (2H, s), 7.91 (1H, d, J=3.43 Hz), 7.90 (1H, s), 6.91 (1H, t,J=8.01 Hz), 6.40-6.36 (3H, m), 4.95 (2H, s), 3.86 (2H, s), 2.47 (3H, s).

Compound 1h-18-14-Methyl-3-(3-aminobenzyl)-7-(pyridin-3-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-12-1, except that compound 1g-18-1was used instead of compound 1g-12-1.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.89 (1H, d, J=1.91Hz), 8.66 (1H, dd, J=4.96, 1.53 Hz), 7.92 (1H, dt, J=8.01, 1.91 Hz),7.72 (1H, d, J=8.01 Hz), 7.54-7.51 (2H, m), 7.42 (1H, dd, J=7.63, 0.30Hz), 7.06 (1H, t, J=8.01 Hz), 6.66 (1H, d, J=8.01 Hz), 6.62 (1H, s),6.52 (1H, dd, J=8.01, 1.91 Hz), 4.01 (2H, s), 2.49 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 343.27 (M+1).

Compound 1h-19-34-Methyl-3-(3-aminobenzyl)-6-chloro-7-(3-methoxyphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-19-3was used instead of compound 1g-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.69 (1H, s), 7.38(1H, t, J=7.63 Hz), 7.32 (1H, s), 7.09-6.96 (4H, m), 6.64 (1H, d, J=7.25Hz), 6.60 (1H, s), 6.52 (1H, dd, J=8.01, 2.29 Hz), 3.99 (2H, s), 3.87(3H, s), 3.62 (2H, bs), 2.46 (3H, s).

Compound 1h-21-34-Methyl-3-(3-aminobenzyl)-6-chloro-7-(5-acetylthiophen-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-21-3was used instead of compound 1g-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.79 (2H, d, J=4.96Hz), 8.17 (1H, s), 7.73 (1H, s), 7.46 (1H, t), 7.13 (2H, m), 6.96 (1H,d, J=7.63 Hz), 4.06 (2H, s), 2.60 (3H, s), 2.41 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 424.09 (M+H).

Compound 1h-22-14-Methyl-3-(3-aminobenzyl)-7-(3-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-12-1, except that compound 1g-22-1was used instead of compound 1g-12-1.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 8.23 (1H, t), 8.05(1H, d, J=8.01 Hz), 7.95 (1H, d, J=8.39 Hz), 7.84 (1H, d, J=1.53 Hz),7.78 (1H, dd, J=8.01 Hz), 7.65 (2H, t), 6.91 (1H, t), 6.43 (3H, m), 4.98(2H, s), 3.85 (2H, s), 2.71 (3H, s), 2.50 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 384.35 (M+1).

Compound 1h-23-14-Methyl-3-(3-aminobenzyl)-7-(4-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-12-1, except that compound 1g-23-1was used instead of compound 1g-12-1.

MS (Micromass, Quattromicro, ESI+) m/z: 413.27 (M+Na).

Compound 1h-1e-1 Trifluoromethanesulfonic acid4-methyl-3-(3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-12-1, except that compound 1g-1e-1was used instead of compound 1g-12-1.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.67 (1H, d, J=8.77Hz), 7.22 (2H, m), 7.05 (1H, t), 6.59 (3H, t, d, J=8.39 Hz), 5.29 (1H,s), 4.02 (2H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 414.10 (M+1).

Compound 1g-28-14-Methyl-3-(3-aminobenzyl)-7-(4-N,N-dimethylaminophenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-12-1, except that compound 1g-28-1was used instead of compound 1g-12-1.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.65 (5H, m), 6.63(2H, d, J=8.77 Hz), 6.65 (2H, s, d, J=8.39 Hz), 6.53 (2H, dd, J=8.6 Hz),4.02 (2H, s), 3.64 (2H, bs), 3.15 (6H, s), 2.43 (3H, s).

Compound 1j-1-5-1 Dimethylcarbamic acid3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

Formic acid (754 μL, 10.0 mmol) was added to chlorosulfonyl isocyanate(1.74 mL, 20.0 mmol) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. Dichloromethane (10 mL) was then added thereto,and the mixture was further stirred for 2 hours. This solution (3.71 mL)was added to a solution of compound 1h-1-5 (2.88 g, 7.42 mmol) andpyridine (1.21 mL, 15 mmol) in dichloromethane (50 mL), and the mixturewas stirred at room temperature for 16 hours. Ethyl acetate was thenadded to the reaction solution, and the solution was washed with sodiumcarbonate solution and saturated saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was distilled awayunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography to yield the title compound (680 mg, 20%).

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.94 (3H, s), 3.08 (3H,s), 3.97 (2H, s), 6.84 (1H, m), 7.00 (1H, dd, J=7.8, 7.8 Hz), 7.10 (2H,brs), 7.33 (1H, m), 7.48 (1H, d, J=6.8 Hz), 7.86 (1H, d, J=11.4 Hz),9.12 (1H, brs).

ESI (LC/MS positive mode) m/z: 468 (M+2H−Na).

Compound 1j-1-5-1Na Dimethylcarbamic acid3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

One equivalent of methanol solution of sodium hydroxide was addeddropwise at room temperature to a mixture of compound 1j-1-5-1 andmethylene chloride. Thirty minutes later, the solvent was distilled awayto yield the title compound.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.39 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 3.88 (2H, s), 5.43 (1H, brs), 6.21 (1H, m), 6.67 (1H, m), 7.19 (1H,m), 7.43 (1H, J=6.8 Hz), 7.83 (1H, d, J=11.2 Hz).

ESI (LC/MS positive mode) m/z: 468 (M+2H−Na).

Compound 1j-1-5-1K Dimethylcarbamic acid3-{2-fluoro-3-aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that KOH was usedinstead of NaOH.

¹H NMR (CD₃OD) δ (ppm): 7.67 (1.0H, d, J=11.0 Hz), 7.40-7.25 (2H, m),6.88 (1.0H, t, J=7.9 Hz), 6.64 (1.0H, t, J=7.9 Hz), 4.04 (2.0H, s), 3.15(3H, s), 3.03 (3H, s), 2.44 (3H, s).

ESI (LC/MS positive mode) m/z: 468 (M+2H−K).

Compound 1j-1-1-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-1was used instead of compound 1h-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.43 (3H, s), 3.02 (3H, s), 3.12 (3H,s), 3.98 (2H, s), 6.87-7.09 (5H, m), 7.18 (1H, dd, J=8.1 Hz), 7.60 (1H,d, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 432 (M+H).

Compound 1j-1-2-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-2was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.46 (3H, s), 3.01 (3H, s), 3.15 (3H,s), 4.02 (2H, s), 6.95 (1H, d, J=7.3 Hz), 7.06-7.22 (3H, m), 7.27 (1H,d, J=6.8 Hz), 7.64 (1H, d, J=11.1 Hz).

ESI (LC/MS positive mode) m/z: 450 (M+H).

Compound 1j-1-3-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-3was used instead of compound 1h-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.42 (3H, s), 3.05 (3H, s), 3.22 (3H,s), 3.95 (2H, s), 6.80-7.20 (4H, m), 7.25 (1H, s), 7.60 (1H, s).

ESI (LC/MS positive mode) m/z: 466 (M+H).

Compound 1j-1-4-1 Dimethylcarbamic acid3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-4was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.44 (3H, s), 2.93 (3H, s), 3.07 (3H,s), 3.97 (2H, s), 6.82 (1H, brt, J=8.6 Hz), 6.99 (1H, brt, J=8.6 Hz),7.19 (1H, dd, J=8.9, 2.3 Hz), 7.25 (1H, d, J=2.3 Hz), 7.33 (1H, brt,J=8.6 Hz), 7.86 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 450 (M+H).

Compound 1j-1-4-1Na Dimethylcarbamic acid3-{3-(aminosulfonyl)amino-2-fluoro-benzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-4-1 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.41 (3H, s), 2.93 (3H, s), 3.07 (3H,s), 3.88 (2H, s), 6.18-6.23 (1H, m), 6.67 (1H, dd, J=7.6, 7.9 Hz),7.14-7.22 (2H, m), 7.24 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.6 Hz).

ESI (LC/MS positive mode) m/z: 450 (M+2H−Na).

Compound 1j-1-7-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-7was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.45 (3H, s), 2.96 (3H, s), 3.13 (3H,s), 3.93 (2H, s), 6.83 (1H, d, J=8.1 Hz), 6.94 (1H, s), 7.02-7.05 (2H,m), 7.16 (1H, dd, J=8.1, 8.1 Hz), 7.38 (1H, s), 8.24 (1H, s).

ESI (LC/MS positive mode) m/z: 558 (M+H).

Compound 1j-1-7-1Na Dimethylcarbamic acid3-{3-(sulfamoylamino)benzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-7-1 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 2.96 (3H, s), 3.13 (3H,s), 3.83 (2H, s), 6.36 (1H, d, J=7.6 Hz), 6.68 (1H, s), 6.77 (1H, d,J=7.9 Hz), 6.88 (1H, dd, J=7.6, 7.9 Hz), 7.35 (1H, s), 8.20 (1H, s).

ESI (LC/MS positive mode) m/z: 558 (M+2H−Na).

Compound 1j-1-7-1K Dimethylcarbamic acid3-{3-(sulfamoylamino)benzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-7-1 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.45 (3H, s), 2.96 (3H, s), 3.13 (3H,s), 3.85 (2H, s), 6.48 (1H, d, J=7.8 Hz), 6.74 (1H, s), 6.83 (1H, d,J=7.6 Hz), 6.95 (1H, dd, J=7.6, 7.8 Hz), 7.36 (1H, s), 8.21 (1H, s).

ESI (LC/MS positive mode) m/z: 558 (M+2H−K).

Compound 1j-1-8-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-8was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.22 (3H, s), 2.45 (3H, s), 2.94 (3H,s), 3.09 (3H, s), 3.93 (2H, s), 6.83 (1H, d, J=8.1 Hz), 6.95 (1H, s),7.02-7.05 (2H, m), 7.16 (1H, dd, J=8.1, 8.1 Hz), 7.21 (1H, s), 7.75 (1H,s).

ESI (LC/MS positive mode) m/z: 446 (M+H).

Compound 1j-1-9-1 Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-1-9was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.97 (3H, s), 3.12 (3H, s), 3.94 (2H,s), 6.84 (1H, d, J=8.1 Hz), 6.97 (1H, s), 7.02-7.05 (2H, m), 7.16 (1H,dd, J=8.1, 8.1 Hz), 7.60 (1H, s), 8.46 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 457 (M+H).

Compound 1j-1-4-1F Dimethylcarbamic acid3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

Chlorosulfonyl isocyanate (0.150 mL) and formic acid (0.065 mL) weremixed at 0° C., and the mixture was stirred at room temperature for 1hour. Dichloromethane (1.2 mL) was added to this mixture and dissolved,and the mixture was further stirred at room temperature for 4 hours.0.060 mL was taken from the solution, and added at 0° C. to a solutionof dimethylcarbamic acid3-(3-amino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester (compound 1h-1-4F) (25.2 mg) in dichloromethane (1.0 mL)/pyridine(0.0065 mL), and the mixture was stirred at room temperature for 3hours. Saturated sodium hydrogen carbonate was then added to thereaction solution, and the mixture was extracted with ethyl acetate, Theextracted liquid was washed with saturated saline, and the organic layerwas dried over anhydrous magnesium sulfate. The solvent was distilledaway under reduced pressure, and the resultant residue was purified bythin layer silica gel chromatography (aminogel)(dichloromethane:methanol=90:10) to yield the title compound (12.0 mg).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.07 (3H, s), 4.06 (2H,s), 5.84 (2H, d, J=45.8 Hz), 6.84 (1H, brt, J=7.7 Hz), 7.01 (1H, brt,J=7.7 Hz), 7.12 (1H, brs), 7.29-7.40 (2H, m), 7.92 (1H, dd, J=8.9, 2.1Hz), 9.15 (1H, brs).

ESI (LC/MS positive mode) m/z: 468 (M+H).

Compound 1j-1-3-1F-Other Dimethylcarbamic acid3-{3-((tert-butoxycarbonyl)aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

Triethylamine (34 μL, 0.25 mmol) andN-(tert-butoxycarbonyl)-N-{4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl}azanide(49 mg, 0.16 mmol) were added in series to a solution ofdimethylcarbamic acid3-(3-aminobenzyl)-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester (compound 1h-1-3F) (33 mg, 0.082 mmol) in anhydrousdichloromethane (1.0 mL), and the mixture was stirred at roomtemperature overnight. The reaction mixture was then poured into waterand extracted with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate. A crude solid wasthen obtained by vacuum concentration, and purified by preparative TLC(ethyl acetate:hexane=1:2) to yield the title compound (30 mg, 63%) as awhite powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.07 (s, 1H), 7.56 (s, 1H), 7.20-6.80(m, 6H), 5.86 (d, J=46.2 Hz, 2H), 4.03 (s, 2H), 3.11 (s, 3H), 2.95 (s,3H), 1.29 (s, 9H).

ESIMS m/z: 528 (M-tBu+2H).

Compound 1j-1-3-1F Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

Trifluoroacetic acid (0.1 mL) was added to a solution ofdimethylcarbamic acid3-{3-((tert-butoxycarbonyloxy)aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester (compound 1j-1-3-1F-other) (23 mg, 0.039 mmol) in anhydrousdichlromethane (1.0 mL), and the mixture was stirred at room temperaturefor 3 hours. The reaction mixture was then poured into saturated sodiumhydrogen carbonate and extracted with ethyl acetate. The organic extractwas washed with saturated saline and dried over magnesium sulfate. Acrude solid was then obtained by vacuum concentration, and purified bypreparative TLC (ethyl acetate:hexane=1:1) to yield the title compound(19 mg, 100%) as a pale yellow powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 9.40(brs, 1H), 8.07 (s, 1H), 7.56 (s,1H), 7.17 (t, J=8.0 Hz, 1H), 7.05 (s+d, 3H), 6.96 (s, 1H), 6.82 (d,J=7.3 Hz, 1H), 5.86 (d, J=46.2 Hz, 2H), 4.03 (s, 2H), 3.11 (s, 3H), 2.95(s, 3H).

ESIMS m/z: 484 (M+H).

Compound 1j-1-1-1F Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1-1F was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.07 (3H, s), 4.02 (2H,s), 5.83 (2H, d, J=46.0 Hz), 6.81 (1H, brd, J=7.4 Hz), 6.96 (1H, brs),7.05 (3H, m), 7.15 (1H, d, J=7.6 Hz), 7.22 (1H, dd, J=8.7, 2.3 Hz), 7.30(1H, d, J=2.3 Hz), 7.91 (1H, dd, J=8.7, 2.3 Hz), 9.39 (1H, brs).

ESI (LC/MS positive mode) m/z: 450 (M+H).

Compound 1j-1-2-1F Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1-2F was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.94 (3H, s), 3.09 (3H, s), 4.03 (2H,s), 5.82 (2H, d, J=46.0 Hz), 6.81 (1H, d, J=8.1 Hz), 6.96 (1H, s), 7.05(2H, m), 7.17 (1H, t, J=7.7 Hz), 7.54 (1H, d, J=6.9 Hz), 7.89 (1H, d,J=9.7 Hz), 9.36 (1H, brs).

ESI (LC/MS positive mode) m/z: 468 (M+H).

Compound 1j-1-3-1OMe Dimethylcarbamic acid3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-methoxymethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound7d-1-3OMe was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.38 (s, 1H), 8.01 (s, 1H), 7.50 (s,1H), 7.17 (t, 1H, J=8.0 Hz), 7.06-6.95 (m, 4H), 6.82 (d, 1H, J=7.3 Hz),4.72 (s, 2H), 4.00 (s, 2H), 3.34 (s, 3H), 3.10 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 496 (M+H).

Compound 1j-1-36-1 Dimethylcarbamic acid3-{(3-aminosulfonyl)amino-4-fluorobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

Compound 1j-1-1-1 (300 mg, 0.70 mmol) and N,N-difluoro-2,2′-bipyridiniumbis(tetrafluoroborate) (256 mg, 0.70 mmol) were stirred in acetonitrileat 50° C. for 10 hours. The title compound was obtained by silica gelchromatography with a mixed solvent of ethyl acetate and hexane.

¹H-NMR (270 MHz, THF-d₈) δ (ppm): 2.96 (3H, s), 3.08 (3H, s), 4.00 (2H,s), 6.29 (2H, br), 6.96 (2H, m), 7.10 (2H, m), 7.58 (1H, d, J=8.2 Hz),7.72 (1H, d, J=8.6 Hz), 8.30 (1H, br).

One of the methyl peaks was overlapped with the peak for the solvent.

ESI (LC-MS positive mode) m/z: 450 (M+H).

Compound 1j-1-37-1 Dimethylcarbamic acid3-{(3-aminosulfonyl)amino-6-fluorobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was obtained as a separate fraction from columnchromatography of the reaction mixture for compound 1j-1-36-1.

¹H-NMR (270 MHz, CD₃OD) δ (ppm): 2.50 (3H, s), 3.03 (3H, s), 3.15 (3H,s), 4.06 (2H, s), 6.99 (2H, m), 7.20 (3H, m), 7.83 (1H, dd, J=8.6, 0.7Hz).

ESI (LC-MS positive mode) m/z: 450 (M+H).

Compound 1j-1-38-1 Dimethylcarbamic acid3-(3-(aminosulfonyl)aminobenzyl)-6-carbamoyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1-38 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.90 (3H, s), 3.05 (3H, s), 3.95 (2H,s), 6.83 (1H, d, J=7.4 Hz), 6.95-7.08 (4H, m), 7.17 (1H, dd, J=7.4, 8.1Hz), 7.29 (1H, s), 7.50 (1H, brs), 7.81 (1H, brs), 8.00 (1H, s), 9.37(1H, brs).

The CH₃ peak was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 475 (M+H).

Compound 1j-1-39-1 Dimethylcarbamic acid3-(3-(aminosulfonyl)aminobenzyl)-4-methyl-2-oxo-6-trimethylsilanylethynyl-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1-39 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.23 (9H, s), 2.46 (3H, s), 2.94 (3H,s), 3.10 (3H, s), 3.93 (2H, s), 6.83 (1H, d, J=7.8 Hz), 6.93-7.09 (4H,m), 7.16 (1H, t, J=7.8 Hz), 7.15 (1H, s), 7.70 (1H, s), 9.13 (1H, brs).

ESI (LC/MS positive mode) m/z: 528 (M+H).

Compound 1j-1-40-1 Dimethylcarbamic acid3-(3-(aminosulfonyl)aminobenzyl)-6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1-40 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.46 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 3.93 (2H, s), 4.45 (1H, s), 6.84 (1H, d, J=7.4 Hz), 6.96 (1H, s),6.96-7.12 (3H, m), 7.16 (1H, t, J=7.9 Hz), 7.38 (1H, s), 7.99 (1H, s),9.36 (1H, brs).

ESI (LC/MS positive mode) m/z: 456 (M+H).

Compound 1j-1-72-1 Dimethylcarbamic acid3-(3-(aminosulfonyl)aminobenzyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except thatdimethylcarbamic acid3-(3-aminobenzyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl ester(compound 1h-1-72) was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 2.95 (3H, s), 3.06 (3H,s), 3.94 (2H, s), 6.85 (1H, d, J=7.6 Hz), 6.90-7.22 (1H, brs), 6.97 (1H,s), 7.04 (1H, d, J=7.8 Hz), 7.17 (1H, dd, J=7.6, 7.8 Hz), 7.27 (1H, d,J=8.1 Hz), 8.43 (1H, d, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 433 (M+H).

Compound 1j-1d-1-1 Pyrrolidine-1-carboxylic acid3-(3-(aminosulfonyl)aminobenzyl)-4-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-1d-1 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.84-1.94 (4H, m), 2.46 (3H, s), 3.36(2H, t, J=6.6 Hz), 3.52 (2H, t, J=6.6 Hz), 3.93 (2H, s), 6.84 (1H, d,J=7.3 Hz), 6.94-7.08 (4H, m), 7.13-7.21 (2H, m), 7.26 (1H, d, J=2.2 Hz),7.86 (1H, d, J=8.7 Hz).

ESI (LC/MS positive mode) m/z: 458 (M+H).

Compound 1j-2-4-13-{2-Fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-2-4was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.46 (3H, s), 3.99 (2H, s), 6.80-6.88(1H, m), 6.97-7.05 (1H, m), 7.06 (2H, br.s), 7.28 (1H, dd, J=8.9, 2.3Hz), 7.30-7.38 (2H, m), 7.38 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=8.9 Hz),8.69 (2H, d, J=4.9 Hz), 9.13 (1H, br.s).

ESI (LC/MS positive mode) m/z: 457 (M+H).

Compound 1j-2-4-1Na3-{2-Fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-1 was used instead of compound 1j-1-5-1.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.43 (3H, s), 3.89 (2H, s), 6.12-6.21(1H, m), 6.60-6.70 (1H, m), 7.13-7.29 (2H, m), 7.33 (1H, t, J=4.8 Hz),7.36 (1H, d, J=2.3 Hz), 7.88 (1H, d, J=8.9 Hz), 8.69 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 457 (M+2H−Na).

Compound 1j-2-4-1K3-(3-Sulfamoylamino-2-fluorobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-1 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 3.91 (2H, s), 6.27-6.32(1H, m), 6.73 (1H, dd, J=7.7, 7.9 Hz), 7.18.-7.27 (2H, m), 7.33 (1H, t,J=4.8 Hz), 7.37 (1H, d, J=2.3 Hz), 7.89(1H, d, J=8.9 Hz), 8.69 (1H, d,J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 457 (M+2H−K).

Compound 1j-3-1-13-{3-(Aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

[Chemical Formula 78]

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-3-1was used instead of compound 1h-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.49 (3H, s), 4.04 (2H, s), 6.92 (1H,d, J=3.8 Hz), 7.04-7.09 (3H, m), 7.11-7.14 (1H, m), 7.22-7.31 (3H, m),7.67 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 444 (M+H).

Compound 1j-3-3-13-{3-(Aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-3-3was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 3.95 (2H, s), 6.84 (1H, d, J=6.9 Hz),6.97 (1H, s), 7.02-7.05 (2H, m), 7.17 (1H, dd, J=6.9, 6.9 Hz), 7.29 (1H,d, J=3.7 Hz), 7.34 (1H, d, J=3.7 Hz), 7.75 (1H, s), 8.12 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 478 (M+H).

Compound 1j-3-4-13-{2-Fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-3-4was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.46 (3H, s), 3.98 (2H, s), 6.82-6.87(1H, m), 6.98-7.04 (1H, m), 7.10 (1H, brs), 7.31-7.39 (4H, m), 7.49 (1H,d, J=2.0 Hz), 7.95 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 462 (M+H).

Compound 1j-3-4-1Na3-(3-Sulfamoylamino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-4-1 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 3.89 (2H, s), 6.20-6.25(1H, m), 6.68 (1H, dd, J=7.9, 8.1 Hz), 7.19 (1H, dd, J=8.2, 8.4 Hz),7.33-7.37 (3H, m), 7.48 (1H, d, J=2.5 Hz), 7.92 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 462 (M+2H−Na).

Compound 1j-3-4-1K3-(3-Sulfamoylamino-2-fluorobenzyl)-4-methyl-7-thiazol-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-4-1 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 3.92 (2H, s), 6.39-6.45(1H, m), 6.79 (1H, dd, J=7.1, 8.1 Hz), 7.24 (1H, dd, J=7.9, 8.1 Hz),7.34-7.38 (3H, m), 7.48 (1H, d, J=2.4 Hz), 7.92 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 462 (M+2H−K).

Compound 1j-3-8-13-{3-(Aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound 1h-3-8was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.26 (3H, s), 2.46 (3H, s), 3.93 (2H,s), 6.83 (1H, d, J=7.7 Hz), 6.93-7.10 (3H, m), 7.16 (1H, dd, J=7.7, 7.7Hz), 7.26-7.30 (2H, m), 7.44 (1H, s), 7.85 (1H, s),

ESI (LC/MS positive mode) m/z: 458 (M+H).

Compound 1j-3-6-13-{2-Chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

At the synthesis of compound 1j-3-4-1, the title compound was isolatedas a byproduct thereof.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.39 (3H, s), 4.03 (2H, s), 6.79 (1H,d, J=6.8 Hz), 7.12-7.20 (3H, m), 7.35-7.44 (4H, m), 7.52 (1H, d, J=2.5Hz), 7.96 (1H, d, J=9.2 Hz), 8.66 (1H, s).

ESI (LC/MS positive mode) m/z: 478 (M+H).

Compound 1j-16-1-1 4-Methyl-3-(3-(aminosulfonyl)aminobenzyl)-7-(thiazol-5-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-16-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d6) δ (ppm): 9.17 (1H, s), 8.53(1H, s), 7.89 (1H, d, J=8.39 Hz), 7.79 (1H, s), 7.68 (1H, dd, J=8.39,1.91 Hz), 7.17 (1H, t, J=7.63 Hz), 7.03 (1H, d, J=9.54 Hz), 6.99 (1H,s), 6.84 (1H, d, J=7.63 Hz), 3.95 (2H, s), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 450.02 (M+Na).

Compound 1j-17-1-14-Methyl-3-(3-(aminosulfonyl)aminobenzyl)-7-(thiazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-17-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 8.03 (1H, d, J=3.05Hz), 7.96 (2H, s), 7.92 (2H, s), 7.17 (1H, t, J=6.87 Hz), 7.06-6.99 (3H,m), 6.86 (1H, dd, J=8.39, 1.91 Hz), 3.95 (2H, s), 2.50 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 449.88 (M+Na).

Compound 1j-20-1-14-Methyl-3-(3-(aminosulfonyl)aminobenzyl)-7-(1-methyl-1H-imidazol-2-yl)-2-oxo-2H-1-benzopyran

Compound 1h-20-1(4-methyl-3-(3-aminobenzyl)-7-(1-methyl-1H-imidazol-2-yl)-2-oxo-2H-1-benzopyran)was synthesized under the same conditions as in the manufacturingexample for compound 1h-1-5, except that compound 1g-20-1 was usedinstead of compound 1g-1-5.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-20-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 7.93 (1H, d, J=8.39Hz), 7.75 (1H, d, J=8.39 Hz), 7.70 (1H, s), 7.34 (1H, s), 7.17 (1H, t,J=7.63 Hz), 7.05 (1H, s), 7.03 (1H, d, J=6.10 Hz), 6.99 (1H, s), 6.84(1H, d, J=7.63 Hz), 3.97 (2H, s), 3.85 (3H, s), 2.50 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 424.95 (M+1).

Compound 1j-32-1-14-Methyl-3-(3-(aminosulfonyl)aminobenzyl)-7-(3-methyl-3H-imidazol-4-yl)-2-oxo-2H-1-benzopyran

Compound 1h-32-1(4-methyl-3-(3-aminobenzyl)-7-(3-methyl-3H-imidazol-4-yl)-2-oxo-2H-1-benzopyran)was synthesized under the same conditions as in the manufacturingexample for compound 1h-1-5, except that compound 1g-32-1 was usedinstead of compound 1g-1-5.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1, except that compound1h-32-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 9.34 (1H, s), 7.89(1H, J=8.7 Hz), 7.78 (1H, s), 7.54 (2H, m), 7.27 (1H, s), 7.17 (1H, t,J=8.1 Hz), 7.02 (4H, m), 6.85 (1H, d, J=7.8 Hz), 3.95 (2H, s), 3.78 (2H,s), 2.48 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 425.01 (M+1).

Compound 1j-1-5-2 Dimethylcarbamic acid6-fluoro-4-methyl-3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

N-(N-methylsulfamoyl)-2-oxazolidinone (27.0 mg, 0.15 mmol) was added toan acetonitrile solution (4 mL) of compound 1h-1-5 (26 mg, 0.07 mmol),and the mixture was stirred at 80° C. for 18 hours. Ethyl acetate wasthen added to the reaction solution, and the solution was washed withsodium carbonate solution and saturated saline. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was distilledaway under reduced pressure. The resultant residue was purified bysilica gel column chromatography to yield the title compound (14.7 mg,45%).

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.43 (3H, s), 2.53 (3H, d, J=5.1 Hz),2.94 (3H, s), 3.09 (3H, s), 3.98 (2H, s), 6.88 (1H, dd, J=6.3, 7.9 Hz),7.01 (1H, dd, J=7.9, 7.9 Hz), 7.22 (1H, q, J=5.1 Hz), 7.27 (1H, dd,J=9.6, 8.2 Hz), 7.48 (1H, d, J=6.8 Hz), 7.86 (1H, d, J=11.4 Hz), 9.38(1H, s).

ESI (LC/MS positive mode) m/z: 482 (M+H).

Compound 1j-1-3-2 Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

Sulfuryl chloride (2.04 mL, 24.8 mmol) was dissolved in dichloromethane(120 mL), and a methylamine THF solution (11.64 mL, 23.3 mmol) anddimethylaminopyridine (also referred to as “DMAP” herein) (2.84 g, 23.3mmol) were added thereto at −78° C. The mixture was stirred at roomtemperature for 2 hours to yield the corresponding sulfamoyl chloride.Dimethylcarbamic acid3-(3-aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester(compound 1h-1-3) (3.0 g, 7.76 mmol), pyridine (3.2 mL) anddichloromethane (60 mL) were added to the reaction solution, and themixture was stirred at room temperature overnight. Water was then addedto the reaction solution, and the solution was extracted withdichloromethane. After washing with sodium hydrogen carbonate solutionand saturated saline, the organic layer was dried over anhydrousmagnesium sulfate, and the solvent was distilled away under reducedpressure. The resultant residue was purified by silica gel columnchromatography to yield the title compound (540 mg).

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.44 (3H, s), 2.68 (3H, d, J=5.1 Hz),3.05 (3H, s), 3.17 (3H, s), 4.02 (2H, s), 4.57 (1H, m), 6.54 (1H, br),6.90-7.00 (2H, m), 7.09 (1H, brs), 7.19-7.30 (1H, m), 7.66 (1H, s).

ESI (LC/MS positive mode) m/z: 480 (M+H).

Compound 1j-1-3-2Na Dimethylcarbamic acid6-chloro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.28 (3H, s), 2.43 (3H, s), 2.95 (3H,s), 3.11 (3H, s), 3.80 (2H, s), 4.78 (1H, br), 6.29 (1H, d, J=8.1 Hz),6.66 (1H, brs), 6.73 (1H, d, J=8.1 Hz), 6.82 (1H, dd, J=8.1, 8.1 Hz),7.46 (1H, s), 7.97 (1H, s).

ESI (LC/MS positive mode) m/z: 480 (M+2H−Na).

Compound 1j-1-3-2K Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (CD₃OD) δ (ppm): 7.91 (1H, d, J=5.6 Hz), 7.32 (1H, s), 7.14-6.98(3H, m), 6.77 (1H, d, J=7.4 Hz), 4.02 (2H, s), 3.18 (3H, s), 3.02 (3H,s), 2.53 (3H, s), 2.48 (3H, s).

ESI (LC/MS positive mode) m/z: 480 (M+2H−K).

Compound 1j-1-1-2 Dimethylcarbamic acid4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound 1h-1-1was used instead of compound 1h-1-3.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.44 (3H, s), 2.64 (3H, d, J=5.1 Hz),3.08 (3H, s), 3.17 (3H, s), 4.01 (2H, s), 4.55-4.65 (1H, m), 6.54-7.30(6H, m), 7.59 (1H, d, J=5.4 Hz).

ESI (LC/MS positive mode) m/z: 446 (M+H).

Compound 1j-1-1S3-2 Dimethylcarbamic acid4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-thioxo-2H-1-benzopyran-7-ylester

50 mg (0.11 mmol) of compound 1j-1-1-2 was dissolved in 1,4-dioxane, and30 mg (0.07 mmol) of Lawson's reagent was added thereto. The mixture washeated under reflux under nitrogen atmosphere for 4 hours. The reactionmixture was purified by HPLC to yield 5 mg (10%) of compound 1j-1-1S3-2as a yellow powder.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (6H, s), 2.95 (3H, s), 3.08 (3H,s), 4.40 (2H, s), 6.83 (1H, d, J=7.6 Hz), 6.96 (1H, s), 7.02 (1H, d,J=7.7 Hz), 7.16 (1H, dd, J=7.7, 7.6 Hz), 7.22 (1H, brs), 7.30 (1H, dd,J=9.0,2.0 Hz), 7.49 (1H, d, J=2.0 Hz), 7.96 (1H, d, J=9.0 Hz), 9.53 (1H,brs).

ESI (LC-MS positive mode) m/z: 462 (M+H).

Compound 1j-1-2-2 Dimethylcarbamic acid6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-1-2was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.47 (3H, s), 2.50 (3H, s), 3.02 (3H,s), 3.15 (3H, s), 4.03 (2H, s), 6.93 (1H, d, J=7.8 Hz), 7.03-7.13 (2H,m), 7.19 (1H, dd, J=7.8, 7.8 Hz), 7.29 (1H, d, J=6.8 Hz), 7.66 (1H, d,J=11.0 Hz).

ESI (LC/MS positive mode) m/z: 464 (M+H).

Compound 1j-1-4-2 Dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluorobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-1-4was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.44 (3H, s), 2.93 (3H, s), 3.07 (3H,s), 3.98 (2H, s), 6.87 (1H, brt, J=7.6 Hz), 7.01 (1H, t, J=7.6 Hz),7.15-7.32 (4H, m), 7.86 (1H, d, J=8.7 Hz), 9.37 (1H, brs).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 464 (M+H).

Compound 1j-1-4-2Na Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)amino-2-fluorobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-4-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.35 (3H, s), 2.41 (3H, s), 2.93 (3H,s), 3.07 (3H, s), 3.88 (2H, s), 6.20-6.25 (1H, m), 6.66 (1H, dd, J=7.7,7.9 Hz), 7.14-7.21 (2H, m), 7.24 (1H, d, J=2.3 Hz), 7.83 (1H, d, J=8.6Hz).

EST (LC/MS positive mode) m/z: 464 (M+2H−Na).

Compound 1j-1-7-2 Dimethylcarbamic acid6-iodo-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-1-7was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.43 (3H, d, J=2.7 Hz), 2.45 (3H, s),2.96 (3H, s), 3.13 (3H, s), 3.93 (2H, s), 6.86 (1H, d, J=8.1 Hz),6.98-7.03 (2H, m), 7.14-7.23 (2H, m), 7.38 (1H, s), 8.24 (1H, s).

ESI (LC/MS positive mode) m/z: 572 (M+H).

Compound 1j-1-7-2Na Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-7-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.34 (3H, s), 2.45 (3H, s), 2.96 (3H,s), 3.13 (3H, s), 3.86 (2H, s), 6.52 (1H, d, J=7.7 Hz), 6.79 (1H, s),6.85 (1H, d, J=7.8 Hz), 6.96 (1H, dd, J=7.7, 7.8 Hz), 7.36 (1H, s), 8.22(1H, s).

ESI (LC/MS positive mode) m/z: 572 (M+2H−Na).

Compound 1j-1-7-2K Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-7-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.36 (3H, s), 2.42 (3H, s), 2.96 (3H,s), 3.14 (3H, s), 3.88 (2H, s), 6.61 (1H, d, J=7.6 Hz), 6.84 (1H, s),6.89 (1H, d, J=8.1 Hz), 7.02 (1H, dd, J=7.6, 8.1 Hz),7.37 (1H, s), 8.22(1H, s).

ESI (LC/MS positive mode) m/z: 572 (M+2H−K).

Compound 1j-1-8-2 Dimethylcarbamic acid6-methyl-4-methyl-3-{3-(methlaminosulfonyl)aminobenzyl}-2oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-1-8was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.23 (3H, s), 2.42 (3H, d, J=5.4 Hz),2.46 (3H, s), 2.94 (3H, s), 3.10 (3H, s), 3.93 (2H, s), 6.86 (1H, d,J=8.1 Hz), 7.00-7.04 (2H, m), 7.14-7.22 (3H, m), 7.75 (1H, s).

ESI (LC/MS positive mode) m/z: 460 (M+H).

Compound 1j-1-8-2Na Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-4,6-dimethyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-8-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.22 (3H, s), 2.32 (3H, s), 2.44 (3H,s), 2.94 (3H, s), 3.09 (3H, s), 3.84 (214, s), 6.44 (1H, d, 7.4 Hz),6.75 (1H, s), 6.81 (1H, d, J=8.1 Hz), 6.91 (1H, dd, J=7.4, 8.1 Hz), 7.20(1H, s), 7.72 (1H, s).

ESI (LC/MS positive mode) m/z: 460 (M+2H−Na).

Compound 1j-1-8-2K Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-4,6-dimethyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-8-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.22 (3H, s), 2.33 (3H, s), 2.44 (3H,s), 2.94 (3H, s), 3.09 (3H, s), 3.84 (2H, s), 6.48 (1H, d, J=7.5, 8.3Hz), 7.19 (1H, s), 7.72 (1H, s).

ESI (LC/MS positive mode) m/z: 460 (M+2H−K).

Compound 1j-1-9-2 Dimethylcarbamic acid6-cyano-4-methyl-3-{3-methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-1-9was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, d, J=5.4 Hz), 2.97 (3H, s),3.12 (3H, s), 3.94 (2H, s), 6.87 (1H, d, J=8.1 Hz), 7.01-7.04 (2H, m),7.15-7.25 (2H, m), 7.60 (1H, s), 8.46 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 471 (M+H).

Compound 1j-1-9-2Na Dimethylcarbamic acid6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-9-2 was used instead of compound 1j-1-5-1.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.42 (s, 1H), 7.57 (s, 1H), 6.82 (t,1H, J=7.5 Hz), 6.74 (d, 1H, J=7.9 Hz), 6.65 (s, 1H), 6.30 (d, 1H, J=7.4Hz), 3.81 (s, 2H), 3.11 (s, 3H), 2.96 (s, 3H), 2.45 (s, 3H), 2.28 (s,3H).

ESIMS m/z: 471 (M+2H−Na).

Compound 1j-1-9-2K Dimethylcarbamic acid6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-9-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.44 (s, 1H), 7.59 (s, 1H), 6.89 (t,1H, J=7.5 Hz), 6.78 (d, 1H, J=7.9 Hz), 6.62 (s, 1H), 6.33 (d, 1H, J=7.4Hz), 3.84 (s, 2H), 3.12 (s, 3H), 2.97 (s, 3H), 2.48 (s, 3H), 2.30 (s,3H).

ESIMS m/z: 471 (M+2H−K).

Compound 1j-1-10-2 Dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-10 was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.40-2.60 (6H, m), 2.93 (3H, s), 3.07(3H, s), 3.96 (2H, s), 6.75-6.84 (2H, m), 6.85-7.10 (1H, brs), 7.18 (1H,dd, J=8.9, 2.4 Hz), 7.27 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=8.6 Hz),8.04-8.10 (1H, m).

ESI (LC/MS positive mode) m/z: 447 (M+H).

Compound 1j-1-11-2 Dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-11 was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.40-2.60 (6H, m), 2.92 (3H, s), 3.04(3H, s), 4.02 (2H, s), 6.75-6.82 (2H, m), 6.82-7.05 (1H, brs), 7.48 (1H,d, J=6.2 Hz), 7.87 (1H, d, J=10.2 Hz), 8.07 (1H, m), 10.00-10.25 (1H,brs).

ESI (LC/MS positive mode) m/z: 465 (M+H).

Compound 1j-1-11-2Na Dimethylcarbamic acid3-(2-(N-methylsulfamoyl)aminopyridin-4-ylmethyl)-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-11-2 was used instead of compound 1j-1-5-1.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.45 (3H, s), 2.50 (3H, s), 2.65 (3H,s), 3.02 (3H, s), 3.95 (2H, s), 6.55 (1H, dd, J=5.1 Hz, J<1.0 Hz), 6.61(1H, brs), 7.30 (1H, d, J=6.8 Hz), 7.67 (1H, d, J=11.1 Hz), 7.90 (1H, d,J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 465 (M+2H−Na).

Compound 1j-1-11-2K Dimethylcarbamic acid3-(2-(N-methylsulfamoyl)aminopyridin-4-ylmethyl)-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-11-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.45 (3H, s), 2.50 (3H, s), 2.65 (3H,s), 3.02 (3H, s), 3.95 (2H, s), 6.55 (1H, dd, J=5.1 Hz, J<1.0 Hz), 6.61(1H, brs), 7.30 (1H, d, J=6.8 Hz), 7.67 (1H, d, J=11.1 Hz), 7.90 (1H, d,J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 465 (M+2H−K).

Compound 1j-1-12-2 Dimethylcarbamic acid4-methyl-3-{2-(methylaminosulfonyl)aminopyridin-4-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-ylester

Dimethylcarbamic acid2-oxo-2H-3-(2-aminopyridin-4-ylmethyl)-4-methyl-6-chloro-1-benzopyran-7-ylester (compound 1h-1-12) was synthesized under the same conditions as inthe manufacturing example for compound 1g-1-5, except that compound5d-0-12 was used instead of compound 1 e-0-5.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-12 was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.51 (3H, s), 2.63 (3H, s), 3.04 (3H,s), 3.18 (3H, s), 4.13 (2H, s), 7.07 (1H, s), 7.08 (1H, d, J=7.8 Hz),7.35 (1H, s), 7.97 (1H, s), 8.12 (1H, d, J=7.8 Hz).

ESI (LC/MS positive mode) m/z: 481 (M+H).

Compound 1j-1-13-2 Dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-13 was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.50 (3H, d, J=8.1 Hz), 3.01 (3H, s),3.13 (3H, s), 4.15 (2H, s), 6.79 (1H, d, J=8.1 Hz), 6.99 (1H, d, J=8.1Hz), 7.10-7.20 (2H, m), 7.63 (1H, dd, J=8.1 Hz), 7.81 (1H, d, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 447 (M+H).

Compound 1j-1-14-2

Dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-fluoro-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-14 was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.25 (3H, d, J=1.9 Hz), 3.01 (3H, s),3.15 (3H, s), 4.15 (2H, s), 6.79 (1H, d, J=8.1 Hz), 7.00 (1H, d, J=8.1Hz), 7.31 (1H, d, J=6.5 Hz), 7.62 (1H, dd, J=8.1 Hz), 7.66 (1H, d,J=11.0 Hz).

ESI (LC/MS positive mode) m/z: 465 (M+H).

Compound 1j-1-15-2 Dimethylcarbamic acid4-methyl-3-{6-(methylaminosulfonyl)aminopyridin-2-ylmethyl}-6-chloro-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-15 was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.50 (3H, brs), 3.02 (3H, s), 3.17 (3H,s), 4.14 (2H, s), 6.79 (1H, d, J=7.6 Hz), 6.99 (1H, d, J=7.6 Hz), 7.32(1H, s), 7.62 (1H, dd, J=7.6 Hz), 7.89 (1H, s).

ESI (LC/MS positive mode) m/z: 481 (M+H).

Compound 1j-1-4-2F Dimethylcarbamic acid3-(3-methylaminosulfonylamino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

Acetonitrile (1.0 mL) was added to dimethylcarbamic acid3-(3-amino-2-fluorobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester (compound 1h-1-4F) (18.5 mg), and triethylamine (0.022 mL) and2-oxo-oxazolidinone-3-sulfonic acid methylamide (19.0 mg) were added tothe resultant suspension while stirring at room temperature. Thesuspension was heated under reflux for 11 hours, triethylamine (0.022mL) and 2-oxo-oxazolidinone-3-sulfonic acid methylamide (19.0 mg) werethen added thereto, and the mixture was further heated under reflux for8 hours. After cooling to room temperature, the reaction solution wasdiluted with a mixed solvent of ethyl acetate and THF (volume ratio1:1). The organic layer was washed with 0.5 M sodium carbonate solutionand saturated saline, and then dried over anhydrous magnesium sulfate.The solvent was distilled away under reduced pressure, and the resultantresidue was purified by thin layer silica gel chromatography (amino gel)(dichloromethane:methanol=95:5) to yield the title compound (9.8 mg).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 2.74 (3H, d, J=5.4 Hz), 3.04 (3H, s),3.13 (3H, s), 4.11 (2H, s), 5.67 (2H, d, J=46.7 Hz), 6.97-7.05 (2H, m),7.10-7.30 (2H, m), 7.37-7.45 (1H, m), 7.78 (1H, dt, J=7.2, 1.8 Hz).

ESI (LC/MS positive mode) m/z: 482 (M+H).

Compound 1j-1-1-2F Dimethylcarbamic acid3-{3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-4-2F, except that compound1h-1-1F was used instead of compound 1h-1-4F.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (3H, d, J=5.1 Hz), 2.93 (3H, s),3.07 (3H, s), 4.02 (2H, brs), 5.84 (2H, d, J=46.2 Hz), 6.84 (1H, brd,J=7.7 Hz), 7.00 (1H, brs), 7.02 (1H, d, J=7.7 Hz), 7.10-7.30 (3H, m),7.31 (1H, d, J=2.3 Hz), 7.91 (1H, dd, J=8.7, 2.3 Hz), 9.56 (1H, brs).

ESI (LC/MS positive mode) m/z: 464 (M+H).

Compound 1j-1-2-2F Dimethylcarbamic acid3-{3-(methylaminosulfonyl)aminobenzyl}-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-4-2F, except that compound1h-1-2F was used instead of compound 1h-1-4F.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (1H, d, J=5.1 Hz), 2.94 (3H, s),3.09 (3H, s), 4.03 (2H, brs), 5.83 (2H, d, J=46.3 Hz), 6.84 (1H, d,J=7.7 Hz), 7.00 (1H, s), 7.02 (1H, brd, J=7.7 Hz), 7.18 (1H, t, J=7.7Hz), 7.23 (1H, q, J=5.1 Hz), 7.54 (1H, d, J=6.8 Hz), 7.89 (1H, dd,J=11.9, 2.3 Hz), 9.55 (1H, brs).

ESI (LC/MS positive mode) m/z: 482 (M+H).

Compound 1j-1-3-2F Dimethylcarbamic acid6-chloro-4-fluoromethyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-4-2F, except that compound1h-1-3F was used instead of compound 1h-1-4F.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 9.57(brs, 1H), 8.07 (s, 1H), 7.56 (s,1H), 7.24 (m, 1H), 7.17 (d, J=7.9 Hz, 1H), 7.04 (d, J=9.1 Hz, 1H), 7.00(s, 1H), 6.84 (d, J=7.3 Hz, 1H), 5.86 (d, J=46.2 Hz, 2H), 4.04 (s, 2H),3.11 (s, 3H), 2.95 (s, 3H), 2.42 (d, J=4.8 Hz, 3H).

ESIMS m/z: 498 (M+H).

Compound 1j-1-3-2FNa Dimethylcarbamic acid3-{3-(methylaminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-2F was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.29 (3H, s), 2.95 (3H, s), 3.11 (3H,s), 3.90 (2H, s), 5.84 (1H, d, J=46.2 Hz), 6.31 (1H, brd, J=7.3 Hz),6.65 (1H, brs), 6.76 (1H, brd, J=7.3 Hz), 6.84 (1H, t, J=7.3 Hz), 7.53(1H, s), 8.02 (1H, s).

ESI (LC/MS positive mode) m/z: 498 (M+2H−Na).

Compound 1j-1-3-2FK Dimethylcarbamic acid3-{3-methylaminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-2F was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.29 (3H, s), 2.95 (3H, s), 3.11 (3H,s), 3.90 (2H, s), 5.84 (1H, d, J=46.2 Hz), 6.31 (1H, brd, J=7.3 Hz),6.65 (1H, brs), 6.76 (1H, brd, J=7.3 Hz), 6.84 (1H, t, J=7.3 Hz), 7.53(1H, s), 8.02 (1H, s).

ESI (LC/MS positive mode) m/z: 498 (M+2H−K).

Compound 1j-1-3-2OH Dimethylcarbamic acid6-chloro-4-(2-hydroxyethyl)-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-4-2F, except that compound7d-1-3OH was used instead of compound 1h-1-4F.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.07 (s, 1H), 7.51 (s, 1H), 7.23 (m,1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.98 (s, 1H), 6.84(d, J=7.3 Hz, 1H), 4.89 (m, 1H), 3.98 (s, 2H), 3.60 (m, 2H), 3.11 (s,3H), 3.00 (m, 2H), 2.95 (s, 3H), 2.42 (d, J=4.8 Hz, 3H).

ESIMS m/z: 510 (M+H).

Compound 1j-1-1-2OH Dimethylcarbamic acid4-(2-hydroxyethyl)-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

Introduction of hydroxymethyl group was performed for compound 1g-1-1under the same conditions as in the manufacturing example for compound7c-1-3OH (to yield compound 7c-1-1OH), and reduction of nitro group wasperformed under the same conditions as in the manufacturing example forcompound 1h-1-5 (to yield compound 7d-1-1OH). Further, sulfamidation wasperformed under the same conditions as in the manufacturing example forcompound 1j-1-4-2F to yield the title compound.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 7.62 (d, J=8.4 Hz, 1H), 7.26 (s, 1H),7.20-6.80 (m, 5H), 5.25 (d, J=5.3 Hz, 1H), 4.00 (s, 2H), 3.58 (m, 2H),3.10 (s, 3H), 3.05 (m, 2H), 3.02 (s, 3H), 2.60 (d, J=4.9 Hz, 3H), 1.79(s, 1H).

ESIMS m/z: 476 (M+H).

Compound 1j-1-3-2CO Dimethylcarbamic acid6-chloro-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-4-2F, except that compound7g-1-3CO was used instead of compound 1h-1-4F.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 9.56 (s, 1H), 7.91 (s, 1H), 7.51 (s,1H), 7.22 (q, J=5.1 Hz, 1H),7.15 (t, J=8.1 Hz, 1H), 7.02 (d, J=8.0 Hz,1H), 6.97 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 4.30 (s, 2H), 3.91 (s, 2H),3.10 (s, 3H), 2.95 (s, 3H), 2.42 (d, J=4.8 Hz, 3H), 2.22 (s, 3H). ESIMSm/z: 522 (M+H).

Compound 1j-1-3-2MeOH Dimethylcarbamic acid6-chloro-4-(2-hydroxypropyl)-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

Reduction of nitro group was performed for dimethylcarbamic acid6-chloro-4-(2-hydroxypropyl)-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester (compound 7c-1-3MeOH) under the same conditions as in themanufacturing example for compound 1h-1-5 (to yield compound7d-1-3MeOH), and sulfamidation was then performed under the samecondition as in the manufacturing example for compound 1j-1-4-2F toyield the title compound.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 9.54 (s, 1H), 8.07 (s, 1H), 7.49 (s,1H), 7.24 (q, J=5.1 Hz, 1H), 7.17 (t, J=8.1 Hz, 1H), 7.03 (d, J=8.0 Hz,1H), 6.97 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.87 (d, J=5.4 Hz, 1H), 4.02(d, J=14.8 Hz, 1H), 3.98 (d, J=14.8 Hz, 1H), 3.85 (m, 1H), 3.10 (s, 3H),3.00 (m, 2H), 2.95 (s, 3H), 2.42 (d, J=4.8 Hz, 3H), 1.21 (d, J=5.5 Hz,3H).

ESIMS m/z: 524 (M+H).

Compound 1j-1-3-2COOMe{3-(3-(Methylaminosulfonyl)aminobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}aceticacid methyl ester

Reduction of nitro group was performed for{3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}aceticacid methyl ester (compound 7f-1-1COOMe) under the same conditions as inthe manufacturing example for compound 1h-1-5 (to yield compound7g-1-1COOMe), and sulfamidation was then performed under the samecondition as in the manufacturing example for compound 1j-1-4-2F toyield the title compound.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 7.76 (d, J=8.7 Hz, 1H), 7.29 (d,J=2.5 Hz, 1H), 7.23-7.13 (m, 3H), 7.03 (d, J=8.1 Hz, 1H), 6.98 (s, 1H),6.81 (d, J=7.6 Hz, 1H), 4.10 (s, 2H), 3.95 (s, 2H), 3.52 (s, 2H), 3.07(s, 3H), 2.93 (s, 2H), 2.43 (d, J=4.8 Hz, 3H).

ESIMS m/z: 504 (M+H).

Compound 1j-1-3-2CONH2 Dimethylcarbamic acid4-carbamoylmethyl-6-chloro-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound7g-1-3CONH2 was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆+CD₃OD (1:4)) δ (ppm): 8.57 (s, ¹H), 8.07 (s,1H), 7.89 (t, 1H, J=8.1 Hz), 7.76-7.73 (m, 2H), 7.65 (d, 1H, J=5.4 Hz),4.72 (s, 2H), 4.63 (s, 2H), 3.81 (s, 311), 3.70 (s, 3H), 3.17 (s, 3H).

ESIMS adz: 523 (M+H).

Compound 1j-1-3-2CONMe2 Dimethylcarbamic acid6-chloro-4-dimethylcarbamoylmethyl-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound7g-1-3CONMe2 was used instead of compound 1h-1-5.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 7.32 (s, 1H), 7.30-7.15 (m, 2H), 6.99(s, 1H), 6.80 (d, 1H, J=7.2 Hz), 6.45 (s, 1H), 6.02 (m, 1H), 3.95 (s,2H), 3.91 (s, 2H), 3.19 (s, 3H), 3.12 (s, 3H), 3.07 (s, 3H), 2.98 (s,3H), 2.56 (s, 3H).

ESIMS m/z: 551 (M+H).

Compound 1j-1-37-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)amino-6-fluorobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-36-1, except that compound1j-1-1-2 was used instead of compound 1j-1-1-1.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.37 (3H, s), 2.44 (3H, s), 2.93 (3H,s), 3.02 (3H, s), 3.93 (2H, s), 6.87 (1H, m), 7.04-7.22 (4H, m), 7.27(1H, br), 7.88 (1H, d, J=10.8 Hz), 9.40 (1H, br).

ESI (LC/MS positive mode) m/z: 464 (M+H).

Compound 1j-1-65-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)amino-6-fluorobenzyl)-4,6-dimethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-36-1, except that compound1j-1-8-2 was used instead of compound 1j-1-1-1.

¹H-NMR (CD₃OD 270 MHz) δ (ppm): 2.30 (3H, s), 2.49 (3H, s), 2.52 (3H,s), 3.02 (3H, s), 3.17 (3H, s), 4.03 (2H, s), 6.99-7.04 (2H, m), 7.22(1H, m), 7.14 (1H, s), 7.71 (1H, s).

EST (LC/MS positive mode) m/z: 478 (M+H).

Compound 1j-1-39-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)aminobenzyl)-4-methyl-2-oxo-6-trimethylsilanylethynyl-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-39 was used instead of compound 1h-1-5.

¹H-NMA (DMSO-d₆, 270 MHz) δ (ppm): 0.24 (9H, s), 2.43 (3H, d, J=4.6 Hz),2.47 (3H, s), 2.95 (3H, s), 3.11 (3H, s), 3.94 (2H, s), 6.63 (1H, d,J=6.9 Hz), 6.74-6.82 (3H, m), 6.89-7.03 (2H, m), 7.15 (1H, s), 7.70 (1H,s).

ESI (LC/MS positive mode) m/z: 542 (M+H).

Compound 1j-1-40-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)aminobenzyl)-6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-40 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, d, J=4.6 Hz), 2.46 (3H, s),2.94 (3H, s), 3.09 (3H, s), 3.93 (2H, s), 4.45 (1H, s), 6.86 (1H, d,J=7.6 Hz), 6.93-7.10 (2H, m), 7.07-7.35 (2H, m), 7.38 (1H, s), 7.99 (1H,s), 9.54 (1H, brs).

ESI (LC/MS positive mode) m/z: 470 (M+H).

Compound 1j-1-72-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)aminobenzyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-ylester

The compound dimethylcarbamic acid3-(3-aminobenzyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl ester(compound 1h-1-72) was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 1g-1-72was used instead of compound 1g-1-5.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-72 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.47 (3H, s), 2.95 (3H,s), 3.06 (3H, s), 3.94 (2H, s), 6.87 (1H, d, J=7.3 Hz), 7.01 (1H, s),7.02 (1H, d, J=7.1 Hz), 7.14-7.20 (2H, m), 7.27 (1H, d, J=8.2 Hz), 8.43(1H, d, J=8.2 Hz), 9.53 (1H, brs).

ESI (LC/MS positive mode) m/z: 447 (M+H).

Compound 1j-1c-1-23-{3-(Methylaminosulfonyl)aminobenzyl}-7-(2-fluoroethoxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1c-1 was used instead of compound 1h-1-5.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.41 (3H, s), 3.90 (2H, s), 4.28-4.33(1H, m), 4.39-4.44 (1H, m), 4.67-4.71 (1H, m), 4.84-4.88 (1H, m), 6.64(1H, d, J=7.6 Hz), 6.99-7.06 (4H, m), 7.16 (1H, dd, J=8.1,7.8 Hz), 7.21(1H, br.s), 7.77 (1H, d, J=8.6 Hz), 9.51 (1H, br.s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC-MS positive mode) m/z: 421 (M+H).

Compound 1j-1d-1-2 Pyrrolidine-1-carboxylic acid3-(3-(methylaminosulfonyl)aminobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1d-1 was used instead of compound 1h-1-5.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.84-1.94 (4H, m), 2.42 (3H, d, J=3.3Hz), 2.46 (3H, s), 3.36 (2H, t, J=6.6 Hz), 3.52 (2H, t, J=6.6 Hz), 3.93(2H, s), 6.86 (1H, d, J=7.8 Hz), 6.98-7.05 (2H, m), 7.13-7.23 (3H, m),7.26 (1H, d, J=2.3 Hz), 7.86 (1H, d, J=8.9 Hz), 9.53 (1H, brs).

ESI (LC/MS positive mode) m/z: 472 (M+H).

Compound 1j-2-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-2-4was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.45 (3H, s), 3.99 (2H, s), 6.83-6.92(1H, m), 6.97-7.06 (1H, m), 7.17 (1H, br.s), 7.34-7.40 (4H, m), 7.91(1H, d, J=8.4 Hz), 8.69 (2H, dd, J=4.8, 1.2 Hz), 9.38 (1H, br.s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 471 (M+H).

Compound 1j-2-4-2Na3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-2 was used instead of compound 1j-1-5-1.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.33 (3H, d, J=3.3 Hz), 2.43 (3H, s),3.89 (2H, s), 6.10-6.19 (1H, m), 6.58-6.66 (1H, m), 7.17 (1H, ddd,J=8.3, 1.5 Hz, J_(HF)=8.3 Hz), 7.25 (1H, dd, J=8.7, 2.3 Hz), 7.33 (1H,t, J=4.8 Hz), 7.37 (1H, d, J=2.3 Hz), 7.88 (1H, d, J=8.7 Hz), 8.69 (2H,d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 471 (M+2H−Na).

Compound 1j-2-4-2K3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 7.88 (d, 1H,J=8.7 Hz), 7.36 (d, 1H, J=2.3 Hz), 7.33 (t, 1H, J=4.8 Hz), 7.25 (dd, 1H,J=8.7, 2.3 Hz), 7.16 (td, 1H, J=8.5, 1.4 Hz), 6.59 (t, 1H, J=7.8 Hz),6.10 (t, 1H, J=6.3 Hz), 4.76 (q, 1H, J=5.8 Hz), 3.88 (s, 2H), 2.43 (s,3H), 2.32 (d, 3H, J=5.6 Hz).

ESI (LC-MS positive mode) m/z: 471 (M+2H−K).

Compound 1j-2-4S1-23-{2-Fluoro-3-methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-ylthio)-2-oxo-2H-1-benzopyran

Compound 1h-2-4S1 was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-2-4S1 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-4S1 was used instead of compound 1h-2-16.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.48 (3H, s), 4.01 (2H, s), 6.83-6.92(1H, m), 6.98-7.05 (1H, m), 7.16 (1H, brs), 7.25-7.35 (2H, m), 7.60 (1H,d, J=8.5 Hz), 7.70-7.74 (1H, m), 7.92 (1H, d, J=8.5 Hz), 8.64 (2H, d,J=4.8 Hz).

ESI (LC-MS positive mode) m/z: 487 (M+H).

Compound 1j-2-4S2-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzothiopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-4S2 was used instead of compound 1h-2-16.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.54 (3H, s), 4.08 (2H, s), 6.70 (1H,dd, J=7.3 Hz, J_(HF)=7.3 Hz), 6.99 (1H, dd, J=7.9 Hz, J_(HF)=7.9 Hz),7.14 (1H, brs), 7.28 (1H, dd, J=8.0, 8.0 Hz), 7.34 (1H, dt, J=4.9, 1.3Hz), 7.40 (1H, dd, J=8.7, 2.2 Hz), 7.64 (1H, d, J=2.4 Hz), 8.16 (1H, d,J=8.7 Hz), 8.70 (2H, dd, J=4.9, 1.2 Hz), 9.44 (1H, brs).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC-MS positive mode) m/z: 487 (M+H).

Compound 1j-2-5-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-2-5was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.40 (3H, s), 2.68 (3H, s), 4.09 (2H,s), 6.78-7.04 (3H, m), 7.17-7.39 (4H, m), 7.70-7.89 (1H, m), 8.61-8.63(2H, m).

ESI (LC/MS positive mode) m/z: 489 (M+H).

Compound 1j-2-6-23-{2-Methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-6 was used instead of compound 1h-2-16.

¹H NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.61 (2H, d, J=4.6 Hz), 7.72(1H, d, J=8.4 Hz), 7.32 (1H, d, J=7.6 Hz), 7.27 (1H, d, J=3.1 Hz), 7.21(1H, dd, J=2.3, 8.4 Hz), 7.13 (1H, t, J=5.0 Hz), 7.07 (1H, t, J=7.8 Hz),6.73 (1H, d, J=7.6 Hz), 6.17 (1H, s), 4.36 (1H, q), 4.03 (2H, s), 2.79(3H, d, J=5.3 Hz), 2.41 (3H, s), 2.38 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 465.08 (M−H).

Compound 1j-2-4-2F3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-2-4F was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 9.36 (s, 1H), 8.68 (d, J=4.9 Hz, 2H),7.96 (dd, J=8.9, 2.2 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.36-7.18 (m, 3H),7.02 (t, J=7.0 Hz, 1H), 6.88 (t, J=7.0 Hz, 1H), 5.86 (d, J=46.2 Hz, 2H),4.07 (s, 2H), 2.51 (d, J=5.1 Hz, 3H).

ESIMS m/z: 489 (M+H).

Compound 1j-2-4-2FNa3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-2F was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.68 (d, J=4.9 Hz, 2H), 7.92 (dd,J=8.9, 2.7 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.32 (t, J=4.7 Hz, 1H), 7.28(dd, J=8.8, 2.3 Hz, 1H), 7.15 (t, J=8.9 Hz, 1H), 6.58 (t, J=7.7 Hz, 1H),6.09 (t, J=7.8 Hz, 1H), 5.81 (d, J=46.2 Hz, 2H), 4.71 (q, J=5.7 Hz, 1H),3.94 (s, 2H), 2.30 (d, J=5.7 Hz, 3H).

ESIMS m/z: 489 (M+2H−Na).

Compound 1j-2-4-2FK3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-4-2F was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 7.94 (dd, 1H,J=8.8, 2.2 Hz), 7.42 (d, 1H, J=2.3 Hz), 7.34 (t, 1H, J=4.7 Hz), 7.30(dd, 1H, J=8.8, 2.3 Hz), 7.18 (t, 1H, J=8.9 Hz), 6.62 (t, 1H, J=7.7 Hz),6.13 (t, 1H, J=7.8 Hz), 5.92 (d, 2H, J=46.2 Hz), 4.80 (q, 1H, J=5.7 Hz),3.96 (s, 2H), 2.33 (d, 3H, J=5.7 Hz).

Compound 1j-2-10-23-{2-(Methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-2-10 was used instead of compound 1h-1-5.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.53 (3H, s), 2.82 (3H, s), 4.18 (2H,s), 7.10-7.35 (4H, m), 7.70-7.80 (2H, m), 8.01 (1H, d, J=6.2 Hz), 8.61(2H, brs).

ESI (LC/MS positive mode) m/z: 454 (M+H).

Compound 1j-2-12-23-{2-(Methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-2-12 was used instead of compound 1h-1-5.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.52 (3H, s), 2.64 (3H, s), 4.11 (2H,s), 7.11 (1H, d, J=6.5 Hz), 7.13 (1H, s), 7.27 (1H, dd, J=4.9 Hz), 7.37(1H, s), 8.00 (1H, s), 8.12 (1H, d, J=6.5 Hz), 8.62 (2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 488 (M+H).

Compound 1j-2-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

Methylamine (158 μL, 317 μmol) and DMAP (38.7 mg, 317 μmol) were addedat −78° C. to a solution of sulfuryl chloride (28 μL, 340 μmol) indichloromethane (2 mL), and the mixture was then stirred at roomtemperature for 2 hours to yield the corresponding sulfamoyl chloride.3-(2-Amino-3-fluoropyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-4-methyl-2-oxo-2H-1-benzopyran(compound 1h-2-16) (60 mg, 159 μmol), pyridine (65 μL, 795 μmol) anddichloromethane (2 mL) were added to the reaction solution, and themixture was stirred at room temperature for 4 hours. After addition ofwater, the organic layer was extracted with dichloromethane. Afterwashing with sodium hydrogen carbonate solution and saturated saline,the organic layer was dried over anhydrous magnesium sulfate, and thesolvent was distilled away under reduced pressure. The resultant residuewas purified by silica gel column chromatography to yield the titlecompound (32 mg, 43%).

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.54 (3H, s), 2.62 (3H, s), 4.22 (2H,s), 6.84 (1H, dd, J=5.4 Hz), 7.20-7.30 (3H, m), 7.80-7.95 (2H, m), 8.63(2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 472 (M+H).

Compound 1j-2-16-2Na3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-16-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.30 (3H, s), 2.46 (3H, s), 3.89 (2H,s), 5.68 (1H, brs), 6.09-6.23 (1H, m), 7.20 (1H, dd, J=2.4, 8.7 Hz),7.34 (1H, t, J=4.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.55 (1H, d, J=5.3 Hz),7.90 (1H, d, J=8.7 Hz), 8.69 (1H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 472 (M+2H−Na).

Compound 1j-2-16-2K3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-16-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.36 (3H, s), 2.47 (3H, s), 3.93 (2H,s), 6.26-6.40 (1H, m), 7.27 (1H, dd, J=2.3, 8.6 Hz), 7.34 (1H, t, J=4.8Hz), 7.39 (1H, d, =2.3 Hz), 7.64 (1H, d, J=4.8 Hz), 7.91 (1H, d, J=8.6Hz), 8.69 (1H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 472 (M+2H−K).

Compound 1j-2-16-2a3-{2-(Ethylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that ethylamine wasused instead of methylamine.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 1.11 (3H, t, J=7.2 Hz), 2.54 (3H, s),3.03 (2H, q, J=7.2 Hz), 4.12 (2H, s), 6.84 (1H, dd, J=5.4 Hz), 7.20-7.30(3H, m), 7.80-7.95 (2H, m), 8.63 (2H, d, J=4.6 Hz).

ESI (LC/MS positive mode) m/z: 486 (M+H).

Compound 1j-2-16-2b3-{2-(Isopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that isopropylaminewas used instead of methylamine.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 0.85-1.30 (6H, m), 2.52 (3H, s),3.45-4.20 (1H, m), 4.11 (2H, s), 6.82 (1H, dd, J=5.4 Hz), 7.20-7.30 (3H,m), 7.80-7.95 (2H, m), 8.63 (2H, d, J=4.6 Hz).

ESI (LC/MS positive mode) m/z: 500 (M+H).

Compound 1j-2-17-23-{2-(methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-17 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.40-2.70 (3H, m), 4.03 (2H, s),6.75-6.83 (1H, m), 6.97 (1H, brs), 7.38 (1H, dd, J=4.5 Hz), 7.66 (1H, d,J=6.5 Hz), 7.93 (1H, d, J=11.1 Hz), 7.90-7.95 (1H, m), 8.70 (2H, d,J=4.5), 10.36 (1H, brs).

ESI (LC/MS positive mode) m/z: 490 (M+H).

Compound 1j-2-17-2c3-{2-(Cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-fluoro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-17 was used instead of compound 1h-2-16, and that cyclopropylaminewas used instead of methylamine.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.40-0.60 (4H, m), 2.24-2.35 (1H, m),2.40-2.70 (3H, m), 4.02 (2H, s), 6.75-6.85 (1H, m), 7.38 (1H, dd, J=4.5Hz), 7.66 (1H, d, J=6.5 Hz), 7.93 (1H, d, J=11.1 Hz), 7.90-7.95 (1H, m),8.70 (2H, d, J=4.5).

ESI (LC/MS positive mode) m/z: 516 (M+H). Compound 1j-2-18-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-(2-amino-3-fluoropyridin-4-ylmethyl)-4-methyl-6-chloro-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-2-18) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-18 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-18 was used instead of compound 1h-2-16.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.47 (3H, s), 2.76 (3H, s), 4.08 (2H,s), 6.85 (1H, dd, J=5.1 Hz), 7.13 (1H, dd, J=4.9 Hz), 7.31 (1H, s), 7.73(1H, s), 7.93 (1H, d, J=5.1 Hz), 8.61 (2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 506 (M+H).

Compound 1j-2-19-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-19 was used instead of compound 1h-2-16.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.24 (3H, s), 2.53 (3H, s), 2.62 (3H,s), 4.11 (2H, s), 6.81 (1H, dd, J=5.1 Hz), 7.19 (1H, s), 7.25 (1H, t,J=4.7 Hz), 7.79 (1H, s), 7.92 (1H, d, J=5.1 Hz), 8.61 (2H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 486 (M+H).

Compound 1j-2-19-2Na3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4,6-dimethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-19-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.15 (3H, s), 2.30 (3H, s), 2.45 (3H,s), 3.89 (2H, s), 5.66 (1H, brs), 6.07-6.21 (1H, m), 7.29-7.33 (2H, m),7.54 (1H, d, J=5.3 Hz), 7.82 (1H, s), 8.67 (2H, dd, J=0.9, 4.8 Hz).

ESI (LC/MS positive mode) m/z: 486 (M+2H−Na).

Compound 1j-2-19-2K3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4,6-dimethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-19-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.15 (3H, s), 2.37 (3H, s), 2.47 (3H,s), 3.93 (2H, s), 6.30-6.42 (1H, m), 7.29-7.33 (2H, m), 7.67 (1H, d,J=5.3 Hz), 7.83 (1H, s), 8.67 (2H, dd, J=0.8, 4.8 Hz).

ESI (LC/MS positive mode) m/z: 486 (M+2H−K).

Compound 1j-2-19-2Me3-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-19Me was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.13 (1H, t, J=7.4 Hz), 2.17 (3H, s),2.46 (3H, s), 2.92 (1H, brq, J=7.4 Hz), 4.00 (2H), 6.82 (1H, brt, J=4.9Hz), 7.00 (1H, brq, J=4.8 Hz), 7.32 (1H, t, J=4.8 Hz), 7.34 (1H, s),7.86 (1H, s), 7.93 (1H, d, J=4.9 Hz), 8.67 (2H, d, J=4.8 Hz), 10.36 (1H,s).

One of the methyl peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 500 (M+H).

Compound 1j-2-19-2MeNa3-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-19-2Me was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.12 (1H, t, J=7.4 Hz), 2.16 (3H, s),2.28 (1H, d, J=5.8 Hz), 2.87 (1H, brq, J=7.4 Hz), 3.17 (3H, s), 3.85(2H, s), 5.50 (1H, q, J=5.8 Hz), 6.04 (1H, t, J==5.1 Hz), 7.32 (1H, s),7.32 (1H, t, J=4.8 Hz), 7.50 (1H, d, J=5.1 Hz), 7.82 (1H, s), 8.67 (2H,d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 500 (M+2H−Na).

Compound 1j-2-19-2MeK3-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-ethyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-2-19-2Me was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.12 (1H, t, J=7.4 Hz), 2.16 (3H, s),2.28 (1H, d, J=5.8 Hz), 2.87 (1H, brq, J=7.4 Hz), 3.17 (3H, s), 3.85(2H, s), 5.50 (1H, q, J=5.8 Hz), 6.04 (1H, t, J=5.1 Hz), 7.32 (1H, s),7.32 (1H, t, J=4.8 Hz), 7.50 (1H, d, J=5.1 Hz), 7.82 (1H, s), 8.67 (2H,d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 500 (M+2H−K).

Compound 1j-2-19-2c3-{2-(Cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-19 was used instead of compound 1h-2-16, and that cyclopropylaminewas used instead of methylamine.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.46-0.55 (4H, m), 2.16 (3H, s),2.26-2.37 (1H, m), 4.03 (2H, s), 6.76-6.86 (1H, m), 7.30-7.33 (2H, m),7.54 (1H, brs), 7.85 (1H, s), 7.93 (1H, d, J=5.4 Hz), 8.67 (2H, d, J=4.8Hz), 10.50 (1H, brs).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 512 (M+H).

Compound 1j-2-16-2c3-{2-(Cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except thatcyclopropylamine was used instead of methylamine.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.40-0.60 (4H, m), 2.24-2.35 (1H, m),2.40-2.70 (3H, m), 4.02 (2H, s), 6.75-6.85 (1H, m), 7.28 (1H, dd, J=1.9,8.4 Hz), 7.32 (1H, dd, J=4.5 Hz), 7.39 (1H, d, J=2.4 Hz), 7.52 (1H,brs), 7.93 (1H, d, J=8.4 Hz), 7.90-7.95 (1H, m), 8.69 (2H, d, J=4.5),10.49 (1H, brs).

ESI (LC/MS positive mode) m/z: 498 (M+H).

Compound 1j-2-41-23-{2-(Methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The compound 2-(di-tert-butyloxycarbonyl)amino-3-chloro-4-methylpyridine(compound 5b-0-41) was synthesized using3-chloro-4-methyl-2-aminopyridine under the same conditions as in themanufacturing example for compound 5b-0-13.

The compound2-(di-tert-butyloxycarbonyl)amino-3-chloro-4-bromomethylpyridine(compound 5c-0-41) was synthesized using compound 5b-0-41 under the sameconditions as in the manufacturing example for compound 5c-0-13.

The compound2-{2-(di-tert-butyloxycarbonyl)amino-3-chloropyridin-4-ylmethyl}-3-oxobutyricacid ethyl ester (compound 5t-0-41) was synthesized using compound5c-0-41 under the same conditions as in the manufacturing example forcompound 5t-0-10.

The compound3-(3-chloro-2-aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran(compound 5d-0-41) was synthesized using compound 5t-0-41 under the sameconditions as in the manufacturing example for compound 5d-0-12.

The compound3-(3-chloro-2-aminopyridin-4-ylmethyl)-7-(pyrimidin-2-yloxy)-4-methyl-2-oxo-2H-1-benzopyran(compound 1h-2-41) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-41 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-41 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 4.04 (2H, s), 6.75 (1H,m), 7.29 (1H, dd, J=2.2, 8.9 Hz), 7.34 (1H, t, J=4.8 Hz), 7.41 (1H, d,J=2.2 Hz), 7.65 (1H, brd, J=4.8 Hz), 7.94 (1H, d, J=8.9 Hz), 8.04 (1H,m), 8.69 (2H, d, J=4.8 Hz).

One of the methyl peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 488 (M+H).

Compound 1j-2-45-23-{2-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-45 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 8.94 (1H, s), 8.69 (2H, d,J=5.0 Hz), 7.89 (1H, d, J=8.8 Hz), 7.39 (1H, d, J=2.3 Hz), 7.33 (2H, m),7.26 (1H, dd, J=2.3, 8.8 Hz), 7.23-7.04 (3H, m), 6.91 (1H, d, J=7.6 Hz),4.09 (2H, s), 2.61 (3H, d, J=5.0 Hz), 2.37 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 452.97 (M+H).

Compound 1j-2-46-23-{4-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-46 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.59 (2H, d, J=5.0 Hz), 7.69(1H, d, J=8.7 Hz), 7.23 (3H, m), 7.18 (1H, dd, J=2.1, 8.7 Hz), 7.13-7.09(3H, m), 6.43 (1H, s), 4.40 (1H, m), 4.03 (2H, s), 2.71 (3H, d, J=5.4Hz), 2.48 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 451.03 (M−H).

Compound 1j-2-52-23-(3-(Methylaminosulfonyl)amino-phenoxy)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-52 was used instead of compound 1h-2-16.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 9.67 (1H, bs), 8.69 (2H, d, J=5.0Hz), 7.90 (1H, d, =8.8 Hz), 7.46 (1H, d, J=2.3 Hz), 7.34 (3H, m), 7.19(1H, m), 6.88 (1H, m), 6.82 (1H, m), 6.63 (1H, dd, J=2.3, 8.4 Hz), 2.45(3H, d, J=4.6 Hz), 2.37 (3H, s).

MS (ESI+) m/z: 455.09 (M+H).

Compound 1j-2-53-23-(3-(Methylaminosulfonyl)amino-thiophenoxy)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2-53 was used instead of compound 1h-2-16.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 9.65 (1H, bs), 8.70 (2H, d, J=5.0Hz), 8.00 (1H, d, J=8.8 Hz), 7.44 (1H, d, J=2.7 Hz), 7.35 (2H, m), 7.32(1H, dd, J=2.3, 8.8 Hz), 7.20 (1H, m), 7.00 (1H, m), 6.96 (1H, m), 6.85(1H, m), 2.75 (3H, s), 2.42 (3H, d, J=4.6 Hz).

MS (ESI+) m/z: 471.03 (M+H).

Compound 1j-3-1-23-{3-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-3-1was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.43 (3H, d, J=3.1 Hz), 3.94 (2H, s),6.87 (1H, d, J=7.3 Hz), 6.99-7.05 (2H, m), 7.13-7.25 (2H, m), 7.32-7.40(3H, m), 7.49 (1H, d, J=2.5 Hz), 7.94 (1H, d, J=8.9 Hz).

One of the methyl peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 458 (M+H).

Compound 1j-3-1-2Na3-(3-(N-Methylsulfamoyl)aminobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-1-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 3.91 (2H, s), 6.71 (1H,d, J=7.5 Hz), 6.85-7.04 (2H, m), 7.07 (1H, t, J=7.7 Hz), 7.33-7.38 (3H,m), 7.48 (1H, d, J=2.5 Hz), 7.92 (1H, d, J=8.7 Hz).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 458 (M+2H−Na).

Compound 1j-3-1-2K3-{3-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-1-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 3.86 (2H, s), 6.53 (1H,d, J=6.9 Hz), 6.78-6.85 (2H, m), 6.94 (1H, t, J=7.8 Hz), 7.32-7.38 (3H,m), 7.47 (1H, dd, J=1.2, 2.3 Hz), 7.92 (1H, d, J=8.9 Hz).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 458 (M+2H−K).

Compound 1j-3-3-23-{3-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-3-3was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, d, J=4.9 Hz), 3.95 (2H, s),6.87 (1H, d, J=7.9 Hz), 7.01-7.04 (2H, m), 7.18 (1H, dd, J=7.9, 7.9 Hz),7.25 (1H, d, J=4.9 Hz), 7.29 (1H, d, J=3.8 Hz), 7.34 (1H, d, J=3.8 Hz),7.75 (1H, s), 8.13 (1H, s), 9.56 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 492 (M+H).

Compound 1j-3-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-3-4was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.46 (3H, s), 3.98 (2H, s), 6.85-6.90(1H, m), 6.98-7.04 (1H, m), 7.20 (1H, d, J=5.0 Hz), 7.29 (1H, ddd,J=1.5, 7.8 Hz, J_(HF)=7.8 Hz), 7.34-7.39 (3H, m), 7.49 (1H, d, J=2.5Hz), 7.95 (1H, d, J=8.9 Hz), 9.39 (1H, brs).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 476 (M+H).

Compound 1j-3-4-2Na3-(3-(N-Methylsulfamoyl)amino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-4-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.37 (3H, s), 2.43 (3H, s), 3.89 (2H,s), 5.36 (1H, brs), 6.28-6.32 (1H, m), 6.69 (1H, dd, J=7.8, 8.1 Hz),7.19 (1H, dd, J=7.8, 8.6 Hz), 7.31-7.40 (3H, m), 7.47 (1H, m), 7.92 (1H,d, J=8.6 Hz).

ESI (LC/MS positive mode) m/z: 476 (M+2H−Na).

Compound 1j-3-4-2K3-(3-(N-Methylsulfamoyl)amino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-4-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.40 (3H, s), 2.44 (3H, s), 3.91 (2H,s), 5.66 (1H, brs), 6.37-6.42 (1H, m), 6.75 (1H, dd, J=7.9, 8.0 Hz),7.24 (1H, dd, J=8.0, 8.4 Hz), 7.34-7.38 (3H, m), 7.48 (1H, dd, J=1.3,2.3 Hz), 7.92 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 476 (M+2H−K).

Compound 1j-3-8-23-{3-(Methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound 1h-3-8was used instead of compound 1h-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.26 (3H, s), 2.41 (3H, d, J=4.1 Hz),2.46 (3H, s), 3.93 (2H, s), 6.85 (1H, d, J=7.4 Hz), 6.97-7.04 (2H, m),7.13-7.24 (2H, m), 7.26-7.30 (2H, m), 7.44 (1H, s), 7.85 (1H, s).

ESI (LC/MS positive mode) m/z: 472 (M+H).

Compound 1j-3-8-2Na3-(3-(N-Methylsulfamoyl)aminobenzyl)-4,6-dimethyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-8-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.27 (3H, s), 2.34 (3H, s), 2.46 (3H,s), 3.87 (2H, s), 6.53 (1H, d, J=7.1 Hz), 6.80-6.99 (4H, m), 7.27-7.31(2H, m), 7.44 (1H, s), 7.84 (1H, s).

ESI (LC/MS positive mode) m/z: 472 (M+2H−Na).

Compound 1j-3-8-2K3-(3-(N-Methylsulfamoyl)aminobenzyl)-4,6-dimethyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyranpotassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-8-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.27 (3H, s), 2.34 (3H, s), 2.46 (3H,s), 3.87 (2H, s), 6.53 (1H, d, J=6.9 Hz), 6.79-6.99 (4H, m), 7.27-7.31(2H, m), 7.44 (1H, s), 7.84 (1H, s).

ESI (LC/MS positive mode) m/z: 472 (M+2H−K).

Compound 1j-3-12-23-{2-(Methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-(2-aminopyridin-4-ylmethyl)-4-methyl-6-chloro-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-3-12) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-12 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3-12 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.48 (3H, s), 3.95 (2H,s), 6.74-6.77 (2H, m), 7.25-7.35 (2H, m), 7.75 (1H, s), 8.03 (1H, d,J=4.9Hz), 8.13 (s, 1H).

ESI (LC/MS positive mode) m/z: 493 (M+H).

Compound 1j-3-19-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-{2-amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-3-19) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-18 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3-19 was used instead of compound 1h-2-16.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.34 (3H, s), 2.51 (3H, s), 2.62 (3H,s), 4.10 (2H, s), 6.81 (1H, dd, J=5.1 Hz), 7.13 (1H, d, J=3.8 Hz),7.20-7.30(2H, m), 7.80 (1H, s), 7.92 (1H, d, J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 491 (M+H).

Compound 1j-3-19-2Na3-(2-(N-Methylsulfamoyl)amino-3-fluoropyridin-4-ylmethyl)-4,6-dimethyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyransodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-3-19-2 was used instead of compound 1j-1-5-1.

¹H NMR (DMSO-d₆) δ (ppm): 7.86 (1H, s), 7.50 (1H, d, J=5.2 Hz), 7.45(1H, s), 7.35-7.25 (2H, m), 6.09 (1H, br), 3.87 (2H, s), 2.45 (3H, s),2.28 (3H, s), 2.27 (3H, s).

ESI (LC/MS positive mode) m/z: 491 (M+2H−Na).

Compound 1j-3-19-2c3-{2-(Cyclopropylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3-19 was used instead of compound 1h-2-16, and that cyclopropylaminewas used instead of methylamine.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.47-0.55 (4H, m), 2.23-2.37 (1H, m),2.28 (3H, s), 2.49 (3H, s), 4.02 (2H, s), 6.76-6.87 (1H, m), 7.29 (2H,s), 7.47 (1H, s), 7.55 (1H, brs), 7.89 (1H, s), 7.89-7.94 (1H, m), 10.48(1H, brs).

ESI (LC/MS positive mode) m/z: 517 (M+H).

Compound 1j-3-20-23-{2-(Methylaminosulfonyl)aminopyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-(2-aminopyridin-4-ylmethyl)-7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran(compound 5d-0-20) was synthesized using compound 5t-0-10 and4-methylresorcinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

The compound3-(2-aminopyridin-4-ylmethyl)-7-(thiazol-2-ylmethyl)-6-methyl-4-methyl-2-oxo-2H-1-benzopyran(compound 1h-3-20) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-20 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3-20 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.28 (3H, s), 2.45 (3H, s), 2.47 (3H,s), 3.96 (2H, s), 6.82-6.84 (2H, m), 6.96 (1H, br), 7.27-7.31 (2H, m),7.45 (1H, s), 7.87 (1H, s), 8.07 (1H, d, J=4.3 Hz), 10.25 (1H,br).

ESI (LC/MS positive mode) m/z: 473 (M+H).

Compound 1j-3-20-4{4-[4,6-Dimethyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]pyridin-2-yl}sulfamicacid

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.28 (3H, s), 2.46 (3H, s), 3.90(2H), 6.50-6.55 (1H, m), 7.13 (1H, s), 7.25-7.35 (2H, m), 7.43 (1H, s),7.80-8.00 (3H, m).

ESI (LC/MS positive mode) m/z: 460 (M+H).

Compound 1j-3-44-23-{2-(Methylaminosulfonyl)amino-3-chloropyridin-4-ylmethyl}-4-methyl-6-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-(3-chloro-2-aminopyridin-4-ylmethyl)-7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran(compound 5d-0-44) was synthesized using compound 5t-0-41 and4-methylresorcinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

The compound3-(3-chloro-2-aminopyridin-4-ylmethyl)-7-(thiazol-yloxy)-6-methyl-4-methyl-2-oxo-2H-1-benzopyran(compound 1h-0-44) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-44 was used instead of compound 4a-0-4.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3-44 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₅, 270 MHz) δ (ppm): 2.29 (3H, s), 2.43 (3H, s), 3.17 (3H,dd, J=1.3, 5.3 Hz), 4.03 (2H, s), 6.73 (1H, d, J=3.3 Hz), 9.95 (1H,brs).

ESI (LC/MS positive mode) m/z: 507 (M+H).

Compound 1j-2a-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2a-4 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.44 (2H, s), 7.71 (1H, d,J=8.8 Hz), 7.40 (1H, m), 7.22 (1H, d, J=2.7 Hz), 7.17 (1H, dd, J=2.3,9.2 Hz), 7.0 (2H, m), 6.58 (1H, brs), 4.38 (1H, m), 4.08 (2H, s), 2.76(3H, d, J=5.3 Hz), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 488.76 (M+H).

Compound 1j-2b-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2b-4 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.51 (1H, d, J=5.7 Hz), 7.72(1H, d, J=8.8 Hz), 7.41 (1H, m), 7.20 (1H, d, J=2.3 Hz), 7.15 (1H,J=2.3, 8.8 Hz), 7.01 (2H, m), 6.93 (1H, d, J=5.7 Hz), 6.58 (1H, brs),4.39 (1H, m), 4.09 (2H, s), 2.77 (3H, d, J=5.3 Hz), 2.48 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 504.63 (M+H).

Compound 1j-5-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-5-4 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.66 (1H, d, J=8.8 Hz), 7.40(1H, m), 7.16 (1H, d, J=2.3 Hz), 7.12 (1H, dd, J=2.3, 8.8 Hz), 7.02 (1H,m), 6.97 (1H, m), 6.61 (1H, brs), 5.88 (1H, s), 4.43 (1H, m), 4.08 (2H,s), 3.98 (3H, s), 3.89 (3H, s), 2.76 (3H, d, J=5.3 Hz), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 531.07 (M+H).

Compound 1j-3a-4-23-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3a-4 was used instead of compound 1h-2-16.

¹H NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.74 (2H, m), 7.72 (1H, d,J=8.8 Hz), 7.49 (1H, d, J=2.3 Hz), 7.38 (4H, m), 7.02 (1H, m), 6.99 (1H,m), 6.62 (1H, bs), 4.44 (1H, m), 4.09 (2H, s), 2.76 (3H, d, J=5.3 Hz),2.48 (3H, s).

MS (Micromass, Quattromicro, ESI+) 526.01 (M+H).

Compound 1j-3b-4-2:3-{2-Fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3b-4 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.69 (1H, d, J=8.8 Hz), 7.40(1H, m), 7.30 (1H, d, J=2.3 Hz), 7.24 (1H, dd, J=2.3, 8.8 Hz), 7.20 (1H,s), 7.01 (1H, m), 6.96 (1H, m), 6.61 (1H, brs), 4.43 (1H, m), 4.07 (2H,s), 2.76 (3H, d, J=5.3 Hz), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 553.79 (M), 555.78 (M+2).

Compound 1j-1a-4-2 Dimethylthiocarbamic acid4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-1a-4 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.66 (1H, m), 7.40 (1H, m),7.06 (2H, m), 7.01 (1H, d, J=8.0 Hz), 6.96 (1H, m), 6.58 (1H, m), 4.40(1H, m), 4.07 (2H, s), 3.47 (3H, s), 3.38 (3H, s), 2.76 (3H, d, J=5.3Hz), 2.45 (3H, s).

MS (Micromass, Quattromicro, EST+) m/z: 480.09 (M+H).

Compound 1j-2a-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2a-16 was used instead of compound 1h-2-16.

¹H-NMR (Broker, 300 MHz, CDCl₃) δ (ppm): 8.44 (2H, s), 7.71 (1H, d,J=8.8 Hz), 7.40 (1H, m), 7.22 (1H, d, J=2.7 Hz), 7.17 (1H, dd, J=2.3,9.2 Hz), 7.0 (2H, m), 6.58 (1H, brs), 4.38 (1H, m), 4.08 (2H, s), 2.76(3H, d, J=5.3 Hz), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 488.76 (M+H).

Compound 1j-2b-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-2b-16 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 8.52 (1H, d, J=5.7 Hz),7.96(1H, m), 7.73(1H, J=8.8 Hz), 7.21 (1H, d, J=2.3 Hz), 7.17 (1H, dd,J=2.7, 8.8 Hz), 7.09 (1H, m), 6.94 (1H, d, J=5.7 Hz), 6.90 (1H, m), 5.47(1H, m), 4.09 (2H, s), 2.76 (3H, d, J=5.3 Hz), 2.49 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 505.87 (M), 507.86 (M+2).

Compound 1j-5-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-5-16 was used instead of compound 1h-2-16.

¹H-NMR (Broker, 300 MHz, CDCl₃) δ (ppm): 7.94 (1H, m), 7.67 (1H, d,J=8.8 Hz), 7.18 (1H, d, J=2.3 Hz), 7.14 (1H, dd, J=2.3, 8.8 Hz), 7.09(1H, m), 6.88 (1H, m), 5.89 (1H, s), 5.47 (1H, m), 4.08 (2H, s), 3.98(3H, s), 3.89 (3H, s), 2.76 (3H, d, J=5.3 Hz), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 531.91 (M+H).

Compound 1j-3a-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3a-16 was used instead of compound 1h-2-16.

¹H NMR (Broker, 300 MHz, CDCl₃) δ (ppm): 7.94 (1H, d, J=5.3 Hz), 7.73(3H, m), 7.52 (1H, d, J=2.3 Hz), 7.43 (1H, m), 7.39 (1H, dd, J=2.7, 8.8Hz), 7.33 (1H, m), 7.15 (1H, m), 6.88 (1H, m), 5.48 (1H, m), 4.09 (2H,s), 2.76 (3H, d, J=5.3 Hz), 2.48 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 526.73 (M+H).

Compound 1j-3b-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-3b-16 was used instead of compound 1h-2-16.

¹H-NMR (Bruker, 300 MHz, CDCl₃) δ (ppm): 7.94 (1H, m), 7.70 (1H, d,J=8.8 Hz), 7.32 (1H, d, J=2.3 Hz), 7.26 (1H, d, J=2.7 Hz), 7.20 (1H, s),7.09 (1H, m), 6.89 (1H, m), 5.47 (1H, m), 4.07 (2H, s), 2.76 (3H, d,J=5.3 Hz), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 554.62 (M), 556.54 (M+2).

Compound 1j-4-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrazin-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-{2-amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyrazin-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-4-16) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and thatbromopyrazine was used instead of 2-bromopyrimidine.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-4-16 was used instead of compound 1h-2-16.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 2.52 (3H, s), 4.01 (2H,s), 3.96 (2H, s), 6.72 (1H, d, J=5.0 Hz), 7.10-7.20 (2H, m), 7.78-7.85(2H, m), 8.09 (1H, dd, J=1.3, 2.5 Hz), 8.27 (1H, d, J=2.5 Hz) 8.42 (1H,brs).

ESI (LC/MS positive mode) m/z: 472 (M+H).

Compound 1j-6-16-23-{2-(Methylaminosulfonyl)amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyridin-2-yloxy)-2-oxo-2H-1-benzopyran

The compound3-{2-amino-3-fluoropyridin-4-ylmethyl}-4-methyl-7-(pyridin-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-6-16) was synthesized under the same conditions as in themanufacturing example for compound 1h-2-4 (synthesis scheme 2), exceptthat compound 5d-0-16 was used instead of compound 4a-0-4, and that2-bromopyridine was used instead of 2-bromopyrimidine.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-6-16 was used instead of compound 1h-2-16.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.52 (3H, s), 2.60 (3H, s), 4.09 (2H),6.75 (1H, brt, J=5.3 Hz), 7.07-7.28 (4H, m), 7.73 (1H, m), 7.83-7.95(2H, m), 8.21 (1H, dd, J=1.2, 4.9 Hz).

ESI (LC/MS positive mode) m/z: 471 (M+H).

Compound 1j-2-47-23-(3-(Methylaminosulfonyl)aminobenzyl)-4-hydroxy-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-2-47 was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.51 (s, 1H), 8.68 (d, 2H, J=4.8 Hz),8.00 (d, 1H, J=8.2 Hz), 7.33 (t, 1H, J=4.8 Hz), 7.28 (d, 1H, J=2.1 Hz),7.19 (dd, 1H, J=8.2, 2.6 Hz), 7.13 (d, 1H, J=7.6 Hz), 7.02-7.00 (m, 2H),6.87 (d, 1H, J=7.4 Hz), 3.81 (s, 2H), 2.43 (d, 3H, J=4.9 Hz).

ESIMS m/z: 455 (M+H).

Compound 1j-2-51-23-(3-(Methylaminosulfonyl)aminophenylamino)-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-2-51 was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.42 (s, 1H), 8.69 (d, 2H, J=4.8 Hz),7.83 (d, 1H, J=8.7 Hz), 7.68 (s, 1H), 7.39 (d, 1H, J=2.0 Hz), 7.33 (t,1H, J=4.8 Hz), 7.28 (d, 1H, J=8.7 Hz), 7.14 (d, 1H, J=5.1 Hz), 7.05 (t,1H, J=8.4 Hz), 6.61 (d, 1H, J=8.4 Hz), 6.44 (m, 2H), 2.42 (d, 3H, J=5.4Hz), 2.26 (s, 3H).

ESIMS m/z: 454 (M+H).

Compound 1j-1-59-2 Dimethylcarbamic acid3-(2-(methylaminosulfonyl)aminobenzoylamino)-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-59 was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.67 (s, 1H), 10.33 (s, 1H), 8.07(d, 1H, J=8.1 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.69 (q, 1H, J=4.9 Hz),7.62-6.59 (m, 2H), 7.34 (d, 1H. J=2.3 Hz), 7.26-7.22 (m, 2H), 3.08 (s,3H), 2.95 (s, 3H), 2.48 (d, 3H, J=4.9 Hz), 2.42 (s, 3H).

ESIMS m/z: 475 (M+H).

Compound 1j-20-1-24-Methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-7-(1-methyl-1H-imidazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-20-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 9.57 (1H, s), 7.93(1H, d, J=8.39 Hz), 7.75 (1H, d, J=8.39 Hz), 7.71 (1H, s), 7.34 (1H, s),7.21-7.16 (2H, m), 7.05 (3H, s), 6.88 (1H, d, J=7.25 Hz), 3.97 (2H, s),3.85 (3H, s), 2.50 (3H, s), 2.43 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 439.00 (M+1).

Compound 1j-30-1-2 N-Methyl-N-2-hydroxyethylcarbamic acid4-methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Compound 1j-0-1-2(7-hydroxy-4-methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran)was synthesized under the same conditions as in the manufacturingexample for compound 1j-1-5-2, except that compound 4a-0-1 was usedinstead of compound 1h-1-5.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-31-1-2, except thatN-methyl-N-2-hydroxyethylamine was used instead ofN-methyl-N-carbamoylmethylamine.

¹H-NMR (Broker (ARX-300), 300 MHz, MeOD-d4) δ (ppm): 7.83 (1H, d, J=8.77Hz), 7.25-7.09 (5H, m), 7.03 (1H, d, J=7.25 Hz), 4.06 (2H, s), 3.78 (2H,t), 3.60 (2H, t), 3.22-3.10 (3H, bs), 2.50 (3H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 498.35 (M+Na).

Compound 1j-31-1-2 N-Methyl-N-carbamoylmethylcarbamic acid4-methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Compound 1j-0-1-2(7-hydroxy-4-methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran)was synthesized under the same conditions as in the manufacturingexample for compound 1j-1-5-2, except that compound 4a-0-1 was usedinstead of compound 1h-1-5.

Next, triethylamine (86 μL, 0.62 mmol) and p-NO₂PhCOCl (27 μL, 0.13mmol) were added to a dimethylformamide solution (1 mL) of compound1j-0-1-2 (33.4 mg, 0.09 mmol) at room temperature, and after stirringfor 30 minutes, N-methyl-N-carbamoylmethylamine (33 uL, 0.27 mmol) wasfurther added, and the mixture was stirred for 10 minutes. Water wasthen added, and the organic layer was extracted twice with ethylacetate, and purified by silica gel chromatography (methylenechloride:methanol=20:1) to yield the title compound (18 mg, 41%).

¹H-NMR (Broker (ARX-300), 300 MHz, MeOD-d₄)d (ppm): 7.85 (1H, dd, J=8.39Hz), 7.27-7.10 (5H, m), 6.97 (1H, d, J=7.63 Hz), 4.09 (1H, s), 4.06 (3H,s), 3.30-3.21 (3H, bs), 2.50 (3H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 511.42 (M+1).

Compound 1j-1-3-3 Dimethylcarbamic acid6-chloro-4-methyl-3-{3-(dimethylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-ylester

Compound 1h-1-3 (50 mg, 0.129 mmol) was dissolved in dichloromethane (1mL), and pyridine (42 μL, 0.516 mmol) and dimethylsulfamoyl chloride (41μL, 0.387 mmol) were added thereto. The mixture was stirred at roomtemperature for 24 hours. The solvent in the reaction solution wasdistilled away under reduced pressure, and the resultant residue waspurified by amino gel column chromatography (dichloromethane) to yieldthe title compound (50 mg, 79%) as a white solid.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.45 (3H, s), 2.76 (6H, s), 3.05 (3H,s), 3.22 (3H, s), 4.05 (2H, s), 6.80-7.60 (5H, m), 7.68 (1H, s).

ESI (LC/MS positive mode) m/z: 494 (M+H).

Compound 1j-1-3-3Na Dimethylcarbamic acid3-(3-(N,N-dimethylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-3 was used instead of compound 1j-1-5-1.

¹H NMR (CD₃OD) δ (ppm): 7.90 (1H, s), 7.31 (1H, s), 7.03-6.90 (3H, m),6.65 (1H, d, J=7.4 Hz), 4.01 (2H, s), 3.18 (3H, s), 3.02 (3H, s), 2.61(6H, s), 2.46 (3H, s).

ESI (LC/MS positive mode) m/z: 494 (M+2H−Na).

Compound 1j-1-3-3K Dimethylcarbamic acid3-(3-(N,N-dimethylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-3-3 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (CD₃OD) δ (ppm): 7.90 (1H, s), 7.31 (1H, s), 7.03-6.90 (3H, m),6.65 (1H, d, J=7.4 Hz), 4.01 (2H, s), 3.18 (3H, s), 3.02 (3H, s), 2.61(6H, s), 2.46 (3H, s).

ESI (LC/MS positive mode) m/z: 494 (M+2H−K).

Compound 1j-2-4-33-{2-Fluoro-3-(dimethylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound 1h-2-4was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.48 (3H, s), 2.69 (6H, s), 4.00 (2H,s), 6.88-6.97 (1H, m), 6.97-7.06 (1H, m), 7.24-7.40 (4H, m), 7.91 (1H,J=8.9 Hz), 8.69 (2H, d, J=4.8 Hz), 9.66 (1H, br.s).

ESI (LC/MS positive mode) m/z: 485 (M+H).

Compound 1j-1b-1-33-{3-(Dimethylaminosulfonyl)aminobenzyl}-7-isobutoxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-1b-1 was used instead of compound 1h-1-3.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 0.98 (3H, s), 1.00 (3H, s),1.98-2.10(1H, m), 2.41 (3H, s),2.61 (6H, s), 3.86 (2H, d, J=6.6 Hz),3.90 (2H, s), 6.91 (1H, J=7.8 Hz), 6.94-7.04 (4H, m), 7.18 (1H, dd,J=7.8,7.6 Hz), 7.75 (1H, d, J=9.6 Hz), 9.79 (1H, br.s).

ESI (LC-MS positive mode) m/z: 445 (M+H).

Compound 1j-1c-1-33-{3-(Dimethylaminosulfonyl)aminobenzyl}-7-(2-fluoroethoxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-1c-1 was used instead of compound 1h-1-3.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.43 (3H, s), 2.61 (6H, s), 3.91 (2H,s), 4.28-4.33 (1H, m), 4.40-4.44 (1H, m), 4.67-4.71 (1H, m),4.84-4.89(1H, m), 6.91 (1H, J=7.4 Hz), 6.97-7.06 (4H, m), 7.18 (1H, dd,J=8.0,7.6 Hz), 7.77 (1H, d, J=8.6 Hz), 9.79 (1H, br.s).

ESI (LC-MS positive mode) m/z: 435 (M+H).

Compound 1j-1c-3-33-{3-(Dimethylaminosulfonyl)aminobenzyl}-6-chloro-7-(2-fluoroethoxy)-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-1c-3 was used instead of compound 1h-1-3.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.43 (3H, s), 2.62 (6H, s), 3.91 (2H,s), 4.38-4.43 (1H, m), 4.40-4.45 (1H, m), 4.70-4.75 (1H, m), 4.87-4.92(1H, m), 6.91 (1H, d, J=7.9 Hz), 7.00 (1H, d, J=7.9 Hz), 7.03 (1H, s),7.18 (1H, dd, J=7.9,7.9 Hz), 7.30 (1H, s), 7.93 (1H, s), 9.80 (1H,br.s).

ESI (LC-MS positive mode) m/z: 469 (M+H).

Compound 1j-1d-1-3 Pyrrolidine-1-carboxylic acid3-(3-(dimethylaminosulfonyl)aminobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-2-3, except that compound1h-1d-1 was used instead of compound 1h-1-3.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 1.92-2.04 (4H, m), 2.45 (3H, s), 2.80(6H, s), 3.50 (2H, t, J=6.7 Hz), 3.59 (2H, t, J=6.7 Hz), 4.03 (2H, s),6.37 (1H, brs), 6.97-7.08 (3H, m), 7.12-7.16 (2H, m), 7.19 (1H, d, J=7.4Hz), 7.61 (1H, d, J=9.4 Hz).

ESI (LC/MS positive mode) m/z: 486 (M+H).

Compound 1j-11-3-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(thiophen-3-yl)-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-11-3 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.70 (1H, s), 7.58(1H, dd, J=3.05, 1.53 Hz), 7.42 (1H, dd, J=4.96, 0.60 Hz), 7.38 (1H, s),7.35 (1H, dd, J=4.96, 1.53 Hz), 7.22 (1H, t, J=7.63 Hz), 7.10 (1H, s),7.02 (2H, dd, J=8.01, 1.91 Hz), 6.43 (1H, s), 4.05 (2H, s), 2.82 (6H,s), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 487.25 (M−1).

Compound 1j-12-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(pyridin-4-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-12-1 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.72 (2H, d, J=4.58Hz), 7.75 (1H, d, J=8.77 Hz), 7.59 (1H, s), 7.56 (1H, dd, J=6.87, 1.91Hz), 7.53 (2H, d, J=5.72 Hz), 7.22 (1H, d, J=8.01 Hz), 7.10 (1H, s),7.05 (1H, d, 8.39 Hz), 7.02 (1H, d, J=7.25 Hz), 6.43 (1H, s), 4.08 (2H,s), 2.82 (6H, s), 2.52 (3H, s).

MS (Micromass, Quattromicro, ESI+) mlz: 450.42 (M+1).

Compound 1j-17-1-24-Methyl-3-(3-(methylaminosulfonyl)aminobenzyl)-7-(thiazol-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-17-1 was used instead of compound 1h-1-5.

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 9.53 (1H, s), 8.02(1H, d, J=3.05 Hz), 7.96 (2H, s), 7.92 (2H, d, J=3.43 Hz), 7.17 (2H, t,J=8.01 Hz), 7.02 (2H, s), 6.87 (1H, d, J=7.63 Hz), 3.96 (2H, s), 2.50(3H, s), 2.42 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 463.98 (M+Na).

Compound 1j-18-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(pyridin-3-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-18-1 was used instead of compound 1h-1-3.

¹H-NMR (Broker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.91 (1H, s), 8.67(1H, s), 7.92 (1H, d, J=8.01 Hz), 7.74 (1H, d, J=8.77 Hz), 7.55 (1H, s),7.53 (1H, dd, J=6.10, 1.53 Hz), 7.43 (1H, dd, J=7.25, 0.90 Hz), 7.22(1H, d, J=8.01 Hz), 7.11 (1H, s), 7.05 (1H, d, J=8.01 Hz), 7.02 (1H, dd,J=8.77, 1.91 Hz), 6.40 (1H, s), 4.07 (2H, s), 2.82 (6H, s), 2.52 (3H,s).

MS (Micromass, Quattromicro, ESI+) m/z: 450.44 (M+1).

Compound 1h-19-3-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-6-chloro-7-(3-methoxyphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-19-3 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.71 (1H, s), 7.39(1H, td, J=9.16, 1.14 Hz), 7.32 (1H, s), 7.22 (1H, t, J=8.01 Hz), 7.10(1H, t, J=1.53 Hz), 7.04-6.96 (5H, m), 6.40 (1H, s), 4.06 (2H, s), 3.86(3H, s), 2.82 (6H, s), 2.49 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 511.03 (M−1).

Compound 1h-21-3-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-6-chloro-7-(5-acetylthiophen-2-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-21-3 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.77 (2H, m), 7.44(2H, m), 7.26 (1H, t), 7.02-7.00 (3H, m), 6.76 (1H, s), 4.04 (2H, s),2.81 (6H, s), 2.59 (3H, s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 529.15 (M−H).

Compound 1j-22-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(3-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-22-1 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.22 (1H, s), 8.00(1H, d, J=7.63 Hz), 7.81 (1H, d, J=8.01 Hz), 7.69 (1H, d, J=8.77 Hz),7.62-7.54 (4H, m), 7.22 (1H, t), 7.14-7.00 (2H, m), 6.48 (1H, bs), 3.95(2H, s), 2.81 (6H, s), 2.61 (3H, s), 2.51 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 513.14 (M+Na).

Compound 1j-23-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(4-acetylphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-23-1 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.08 (2H, d, J=8.77Hz), 7.73 (4H, d, J=8.77 Hz), 7.56 (2H, m), 7.19 (3H, m), 6.48 (1H, bs),4.15 (2H, s), 2.81 (6H, s), 2.65 (3H, s), 2.51 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 489.07 (M−1).

Compound 1j-1e-1-3 Trifluoromethanesulfonic acid4-methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-1e-1 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.63 (2H, d, J=8.77Hz), 7.22 (2H, m), 7.09 (3H, m), 6.23 (1H, bs), 4.02 (2H, s), 2.72 (6H,s), 2.46 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 519.14 (M−1).

Compound 1j-24-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(3-cyanophenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound1j-1e-1-3 was used instead of compound 1g-1e-3, and that3-cyanophenylboronic acid was used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.91 (1H, t), 7.82(1H, d, J=7.63 Hz), 7.78-7.65 (2H, m), 7.60 (1H, t), 7.46 (2H, m), 7.20(1H, t), 7.06 (1H, s) 7.03 (2H, t), 6.29 (1H, bs), 4.15 (2H, s), 2.81(6H, s), 2.51 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 474.27 (M+1).

Compound 1j-25-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(2-methoxyphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound1j-1e-1-3 was used instead of compound 1g-1e-3, and that2-methoxyphenylboronic acid was used instead of thiophene-3-boronicacid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.66 (1H, d, J=8.77Hz), 7.58 (2H, dd, J=8.77 Hz), 7.51 (2H, m), 7.25 (1H, t), 7.18 (1H, s),7.05 (4H, m), 6.45 (1H, bs), 4.15 (2H, s), 3.81 (3H, s), 2.81 (6H, s),2.49 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 479.37 (M+1).

Compound 1j-26-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(4-cyanophenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound1j-1e-1-3 was used instead of compound 1g-1e-3, and that4-cyanophenylboronic acid was used instead of thiophene-3-boronic acid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.80-7.70 (5H, m),7.72 (2H, m), 7.22 (1H, t), 7.10 (1H, s) 7.03 (2H, m), 6.29 (1H, bs),4.15 (2H, s), 2.81 (6H, s), 2.51 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 474.27 (M+1).

Compound 1j-27-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(4-methoxyphenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound1j-1e-1-3 was used instead of compound 1g-1e-3, and that4-methoxyphenylboronic acid was used instead of thiophene-3-boronicacid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 8.08 (1H, d, J=8.01Hz), 7.55 (1H, d, J=1.91 Hz), 7.48 (1H, dd, J=8.39 Hz), 7.41-7.32 (2H,m), 7.22 (1H, t), 7.10-6.99 (5H, m), 6.29 (1H, bs), 4.08 (2H, s), 3.84(3H, s), 2.81 (6H, s), 2.51 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 474.27 (M+1).

Compound 1j-28-1-34-Methyl-3-(3-(dimethylaminosulfonyl)aminobenzyl)-7-(4-N,N-dimethylaminophenyl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-3, except that compound1h-28-1 was used instead of compound 1h-1-3.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.61 (5H, m), 7.25(1H, t), 7.15-7.08 (3H, s, t), 6.82 (2H, d, J=8.77 Hz), 6.39 (1H, bs),4.04 (2H, s), 3.02 (6H, s), 2.79 (6H, s), 2.43 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 492.32 (M+1).

Compound 1j-29-1-34-Methyl-3-(3-methylaminosulfonyl)aminobenzyl)-7-(benzo[1,3]dioxol-4-yl)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-11-3, except that compound1j-1e-1-1 was used instead of compound 1g-1e-3, and thatbenzo[1,3]dioxol-4-boronic acid was used instead of thiophene-3-boronicacid.

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.63 (1H, d, J=8.77Hz), 7.46 (2H, m), 7.23 (1H, t), 7.13 (5H, m), 6.92 (1H, d, J=8.01 Hz),6.48 (1H, s), 6.02 (2H, s), 4.04 (2H, s), 2.80 (6H, s), 2.47 (3H, s).

MS (Micromass, Quattromicro, ESI−) m/z: 491.34 (M−1).

Compound 1j-1-21-2 Dimethylcarbamic acid3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

Sulfuryl chloride (66.5 μL, 872 μmol) was dissolved in dichloromethane(4 mL), and 2-cyanoethylamine (57.2 μL, 776 μmol) and DMAP (94.7 mg, 776μmol) were added thereto at −78° C. The mixture was stirred at roomtemperature to yield the corresponding sulfamoyl chloride.Dimethylcarbamic acid3-(3-aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester(100 mg, 258.5 μmol), pyridine (0.5 mL) and dichloromethane (2 mL) wereadded to the reaction solution, and the mixture was stirred at roomtemperature overnight. Water was then added to the reaction solution,and the mixture was extracted with dichloromethane. After washing withsodium hydrogen carbonate solution and saturated saline, the organiclayer was dried over anhydrous magnesium sulfate, and the solvent wasdistilled away under reduced pressure. The resultant residue waspurified by silica gel column chromatography (methanol:methylenechloride=1:20) to yield the title compound (111 mg, 83%).

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.44 (3H, s), 2.44-2.55 (2H, m), 3.04(3H, s), 3.17 (3H, s), 3.15-3.30 (2H, m), 3.99 (2H, s), 6.92-7.15 (3H,m), 7.20 (1H, s), 7.15-7.25 (1H, m), 7.66 (1H, s).

ESI (LC/MS positive mode) m/z: 519 (M+H).

Compound 1j-1-21-2Na Dimethylcarbamic acid3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester sodium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-21-2 was used instead of compound 1j-1-5-1.

¹H NMR (CD₃OD) δ (ppm): 7.89 (1H, s), 7.30 (1H, s), 7.04-6.98 (3H, m),6.70 (1H, d, J=7.4 Hz), 3.99 (2H, s), 3.17 (3H, s), 3.02 (3H, s),2.57-2.52 (2H, m), 2.48 (3H, s).

ESI (LC/MS positive mode) m/z: 519 (M+2H−Na).

Compound 1j-1-21-2K Dimethylcarbamic acid3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester potassium salt

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-1Na, except that compound1j-1-21-2 was used instead of compound 1j-1-5-1, and that KOH was usedinstead of NaOH.

¹H NMR (CD₃OD) δ (ppm): 7.89 (1H, s), 7.30 (1H, s), 7.04-6.98 (3H, m),6.70 (1H, d, J=7.4 Hz), 3.99 (2H, s), 3.17 (3H, s), 3.02 (3H, s),2.57-2.52 (2H, m), 2.48 (3H, s).

ESI (LC/MS positive mode) m/z: 519 (M+2H−K).

Compound 1j-1-22-2 Dimethylcarbamic acid3-(3-(N-(2-hydroxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that 2-aminoethanolwas used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.44 (3H, s), 3.05 (3H, s), 3.12 (2H,m) 3.17 (3H, s), 3.52 (2H, br), 4.02 (2H, s), 6.92-7.05 (2H, m), 7.09(1H, brs), 7.19-7.30 (1H, m), 7.66 (1H, s).

ESI (LC/MS positive mode) m/z: 510 (M+H).

Compound 1j-1-23-2 Dimethylcarbamic acid3-(3-(N-(2-methoxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that2-methoxyethylamine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.44 (3H, s), 3.05 (3H, s), 3.17 (3H,s), 3.15-3.25 (2H, s), 3.41 (3H, s), 3.45-3.55 (2H, m), 4.01 (2H, s),6.95-7.20 (2H, m), 7.09 (1H, s), 7.19-7.30 (1H, in), 7.25 (1H, s), 7.66(1H, s).

ESI (LC/MS positive mode) m/z: 524 (M+H).

Compound 1j-1-24-2 Dimethylcarbamic acid3-(3-(N-(2-aminoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester hydrochloride

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that1,2-ethylenediamine was used instead of 2-cyanoethylamine.

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.51 (3H, s), 2.95-3.05 (2H, m), 3.05(3H, s), 3.14-3.25 (2H, m), 3.17 (3H, s), 4.05 (2H, s), 6.97 (1H, d,J=8.1 Hz), 7.08 (1H, d, J=8.1 Hz), 7.12 (1H, brs), 7.22 (1H, dd, J=8.1Hz), 7.32 (1H, s), 7.93 (1H, s).

ESI (LC/MS positive mode) m/z: 509 (M−Cl).

Compound 1j-1-25-2 Dimethylcarbamic acid3-(3-(N-(2,3-dihydroxypropyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that2,3-dihydroxypropylamine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.38 (3H, s), 3.05 (3H, s), 3.16 (3H,s), 3.30-3.50 (2H, m), 3.52-3.70 (1H, m), 3.89 (2H, s), 6.86 (1H, d,J=7.7 Hz), 6.99 (1H, d, J=7.7 Hz), 7.05 (1H, s), 7.07 (1H, d, J=7.7 Hz),7.13 (1H, s), 7.60 (1H, s).

EST (LC/MS positive mode) m/z: 540 (M+H).

Compound 1j-1-26-2 Dimethylcarbamic acid6-chloro-4-methyl-3-[3-(4-methylpiperazin-1-ylsulfonylamino)benzyl]-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that1-methylpiperazine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.22 (3H, s), 2.25-2.36 (4H, m), 2.43(3H, s), 3.05 (3H, s), 3.18 (3H, s), 3.20-130 (2H, m), 4.01 (2H, s),6.95-7.08 (2H, m), 7.15-7.30 (3H, m), 7.65 (1H, s).

ESI (LC/MS positive mode) m/z: 549 (M+H).

Compound 1j-1-28-2 Dimethylcarbamic acid3-(3-(N-(N′-methyl-2-aminoethyl)-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester hydrochloride

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that2-methylaminoethylamine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.41 (3H, brs), 3.00 (6H, s), 3.05 (3H,brs), 3.17 (3H, brs), 3.50-3.65 (2H, m), 3.65-3.75 (2H, m), 3.98 (2H,brs), 6.70-7.60 (5H, m), 7.60 (1H, brs).

ESI (LC/MS positive mode) m/z: 523 (M−Cl).

Compound 1j-1-29-2 Dimethylcarbamic acid6-chloro-3-[3-(3,4-dihydro-1H-isoquinolin-2-ylsulfonylamino)benzyl]-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that isoquinolinewas used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.30 (3H, s), 2.74 (2H, m), 3.10 (3H,s), 3.17 (3H, s), 3.48 (2H, m), 3.95 (2H, s), 4.42 (2H, s), 6.92-7.27(9H, m), 7.56 (1H, s).

ESI (LC/MS positive mode) m/z: 582 (M+H).

Compound 1j-1-30-2 Dimethylcarbamic acid3-(3-(N-2,2,2-trifluoroethylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that2,2,2-trifluoroethylamine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.45 (3H, s), 3.04 (3H, s), 3.18 (3H,s), 3.55-3.70 (2H, m), 4.02 (2H, s), 7.00-7.10 (3H, m), 7.20-7.30 (1H,m), 7.62 (1H, s).

ESI (LC/MS positive mode) m/z: 548 (M+H).

Compound 1j-1-31-2 Dimethylcarbamic acid3-(3-(N-methoxysulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except thatO-methylhydroxylamine was used instead of 2-cyanoethylamine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 2.45 (3H, s), 3.04 (3H, s), 3.18 (3H,s), 3.76 (3H, s), 4.02 (2H, s), 6.78 (1H, brs), 7.00-7.30 (3H, m), 7.65(1H, s).

ESI (LC/MS positive mode) m/z: 496 (M+H).

Compound 1j-1-32-2 Dimethylcarbamic acid3-[3-(2-acetylamino-ethanesulfonylamino)benzyl]-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

Compound 1h-1-3 (5.8 g, 15 mmol), 2-phthalimidoethanesulfonyl chloride(6.1 g) and triethylamine (10.4 mL) were stirred in dichloromethane atroom temperature overnight. Water was then added to the reactionmixture, and extraction was performed with ethyl acetate. The organicextract was washed with hydrochloric acid, sodium bicarbonate water andsaturated saline. After drying over magnesium sulfate, the mixture wasconcentrated under reduced pressure to yield a crude product, which wasthen purified by column chromatography to yield a compound (9.4 g).

A portion (5.0 g) of the obtained compound and hydrazine monohydrate(0.94 mL) were stirred in an ethanol/THF mixed solvent at roomtemperature overnight. Water was then added to the reaction mixture, andextraction was performed with ethyl acetate. The organic extract waswashed with sodium bicarbonate water and saturated saline. After dryingover magnesium sulfate, the mixture was concentrated under reducedpressure to yield a crude product, which was then purified by columnchromatography to yield a compound (848 mg).

A portion (50.8 mg) of the obtained compound, acetyl chloride (9.5 μL)and triethylamine (28.5 μL) were stirred in methylene chloride at 0° C.for 2 hours. Water was then added to the reaction mixture, andextraction was performed with ethyl acetate. The organic extract waswashed with sodium bicarbonate water and saturated saline. After dryingover magnesium sulfate, the mixture was concentrated under reducedpressure to yield a crude product, which was then purified by columnchromatography to yield the title compound (56 mg). ¹H-NMR (CDCl₃, 270MHz) δ (ppm): 1.88 (3H, s), 2.25 (3H, s), 3.04 (3H, s), 3.10-3.30 (5H,m), 3.50-3.70 (2H, m), 4.00 (2H, s), 6.95-8.00 (6H, m).

ESI (LC/MS positive mode) m/z: 536 (M+H).

Compound 1j-1-33-2 Dimethylcarbamic acid6-chloro-4-methyl-2-oxo-3-[3-(2-oxo-oxazolidine-3-sulfonylamino)benzyl]-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-21-2, except that oxazolidinonewas used instead of 2-cyanoethylamine.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 2.25 (3H, s), 2.95 (3H, s), 3.10 (3H,s), 3.60-3.80 (2H, m), 3.98 (2H, s), 4.10-4.30 (2H, m), 6.95-7.10 (3H,m), 7.25 (1H, t, J=7.7 Hz), 7.50 (1H, s), 8.05 (1H, s), 10.80 (1H, brs).

ESI (LC/MS positive mode) m/z: 536 (M+H).

Compound 1j-1d-1-2 Pyrrolidine-1-carboxylic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-1d-1 was used instead of compound 1h-1-3.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.84-1.94 (4H, m), 2.42 (3H, d, J=3.3Hz), 2.46 (3H, s), 3.36 (2H, t, J=6.6 Hz), 3.52 (2H, t, J=6.6 Hz), 3.93(2H, s), 6.86 (1H, d, J=7.8 Hz), 6.98-7.05 (2H, m), 7.13-7.23 (3H, m),7.26 (1H, d, J=2.3 Hz), 7.86 (1H, d, J=8.9 Hz), 9.53 (1H, brs).

ESI (LC/MS positive mode) m/z: 472 (M+H).

Compound 1j-1-72-2 Dimethylcarbamic acid3-(3-(N-methylsulfamoyl)aminobenzyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-1-72 was used instead of compound 1h-1-3.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 2.47 (3H, s), 2.95 (3H,s), 3.06 (3H, s), 3.94 (2H, s), 6.87 (1H, d, J=7.3 Hz), 7.01 (1H, s),7.02 (1H, d, 7.1 Hz), 7.14-7.20 (2H, m), 7.27 (1H, d, J=8.2 Hz), 8.43(1H, d, J=8.2 Hz), 9.53 (1H, brs).

ESI (LC/MS positive mode) m/z: 447 (M+H).

Compound 1o-2-4-22-{2-Fluoro-3-[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide

Step 1 (Preparation of THF Solution of Compound 1l-1):

2-Propanol (130 μL, 1.69 mmol) was added to a solution of chlorosulfonylacetyl chloride (1180 μL, 1.69 mmol) in THF (3 mL) at 0° C. undernitrogen atmosphere, and the mixture was stirred at 0° C. for 20minutes. The mixture was further stirred at room temperature for 2 hoursto yield a THF solution of compound 1I-1 quantitatively.

Step 2 (Synthesis of Compound 1m-2-4):

A THF solution of compound 1l-1 obtained in step 1 (1.04 mL, 0.585 mmol)was added dropwise under nitrogen atmosphere to a solution of compound1h-2-4 (214.4 mg, 0.568 mmol) and diisopropylethylamine (228 μL, 1.306mmol) in THF (8 mL). After stirring at room temperature for 40 minutes,a solution of sodium hydroxide (46.9 mg, 2.346 mmol) in water (8 mL),and methanol (0.5 mL) were added, and the mixture was stirred for 1hour. Ethyl acetate (40 mL) was then added to the reaction solution, andthe solution was washed twice with 1N hydrochloric acid (20 mL) and oncewith saturated saline (30 mL). The resultant organic layer was driedover sodium sulfate, and the solvent was distilled away under reducedpressure. The resultant residue was purified by silica gelchromatography (dichloromethane:methanol=10:1) to yield compound 1m-2-4(65.9 mg, 23%) as a pale yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.47 (3H, s), 3.67 (2H, s), 4.00 (2H,s), 6.80-6.88 (1H, m), 6.95-7.04 (1H, m), 7.22-7.36 (3H, m), 7.38 (1H,d, J=2.3 Hz), 7.91 (1H, d, J=8.9 Hz), 8.69 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 500 (M+H).

Step 3 (Synthesis of Compound 1o-2-4-2):

N,N-dimethylformamide (1 mL) was added to compound 1m-2-4 (32 mg, 0.064mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.5mg, 0.076 mmol) and 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole(12.4 mg, 0.076 mmol). A 2.0 M methylamine THF solution (96 μL, 0.192mmol) and diisopropylethylamine (22.3 μL, 0.128 mmol) were addedthereto, and the mixture was stirred at room temperature under nitrogenatmosphere for 19 hours. Ethyl acetate (20 mL) was then added to thereaction solution, and the solution was washed twice with 1Nhydrochloric acid (20 mL), three times with saturated sodium hydrogencarbonate solution (20 mL) and further once with saturated saline. Theresultant organic layer was dried over sodium sulfate, and the solventwas distilled away under reduced pressure. The resultant residue waspurified by silica gel column chromatography (methylenechloride:methanol=10:1) and the title compound (9 mg, 28%) was obtainedas a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.48 (3H, s), 2.61 (3H, d, J=4.5 Hz),4.00 (2H, s), 6.95-7.11 (2H, m), 7.25-7.30 (4H, m), 7.92 (1H, d, J=8.9Hz), 8.15-8.23 (1H, m), 8.69 (2H, d, J=4.8 Hz), 9.71 (1H, s).

ESI (LC/MS positive mode) m/z: 513 (M+H).

Compound 1o-1-3-1 Dimethylcarbamic acid3-(3-carbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-3was used instead of compound 1h-2-4 in step 2, and that ammonia was usedinstead of methylamine in step 3.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 2.95 (3H, s), 3.11 (3H,s), 3.86 (2H, s), 3.96 (2H, s), 6.96 (1H, d, J=5.4 Hz), 7.03-7.08 (2H,m), 7.21 (1H, m), 7.34 (1H, br), 7.50 (1H, s), 7.60 (1H, br), 8.02 (1H,s), 9.78 (1H, br).

ESI (LC/MS positive mode) m/z: 508 (M+H).

Compound 1o-1-8-1 Dimethylcarbamic acid3-(3-carbamoylmethanesulfonylamino-benzyl)-4,6-dimethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-8was used instead of compound 1h-2-4, and that ammonia was used insteadof methylamine.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.18 (3H, s), 2.23 (3H, s), 2.94 (3H,s), 3.09 (3H, s), 3.86 (2H, s), 3.95 (2H, s), 6.43-6.69 (1H, m),6.76-7.31 (4H, m), 7.74 (1H, s).

ESI (LC/MS positive mode) m/z: 488 (M+H).

Compound 1o-1-3-2 Dimethylcarbamic acid3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-3was used instead of compound 1h-2-4 in step 2.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 2.56 (3H, d, J=5.4 Hz),2.95 (3H, s), 3.11 (3H, s), 3.87 (2H, s), 3.96 (2H, s), 6.98 (1H, d,J=8.1 Hz), 7.03-7.09 (2H, m), 7.22 (1H, m), 7.50 (1H, s), 8.02 (1H, s),8.14 (1H, d, J=5.4 Hz), 9.78 (1H, br).

ESI (LC/MS positive mode) m/z: 522 (M+H).

Compound 1o-1-8-2 Dimethylcarbamic acid4,6-dimethyl-3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-8was used instead of compound 1h-2-4.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.17 (3H, s), 2.23 (3H, s), 2.94 (3H,s), 3.09 (3H, s), 3.88 (2H, s), 3.95 (2H, s), 6.97 (1H, d, J=8.4 Hz),7.05-7.12 (2H, m), 7.17-7.27 (2H, m), 7.75 (1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 502 (M+H).

Compound 1o-1-40-2 Dimethylcarbamic acid6-ethynyl-4-methyl-3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound1h-1-40 was used instead of compound 1h-2-4.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.17 (3H, s), 2.94 (3H, s), 3.09 (3H,s), 3.88 (2H, s), 3.96 (2H, s), 4.43 (1H, s), 6.99 (1H, d, J=6.3 Hz),7.05-7.13 (2H, m), 7.20-7.26 (2H, m), 7.38 (1H, s), 7.99 (1H, s), 9.77(1H, s).

One of the CH₃ peaks was overlapped with the DMSO peak.

ESI (LC/MS positive mode) m/z: 512 (M+H).

Compound 1o-1-1-3 Dimethylcarbamic acid3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-1was used instead of compound 1 h-2-4, and that dimethylamine was usedinstead of methylamine.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 2.75 (3H, s), 2.94 (6H,s), 3.06 (3H, s), 3.94 (2H, s), 6.92 (1H, d, J=6.5 Hz), 7.00-7.25 (5H,m), 7.83 (1H, d, J=7.8 Hz).

ESI (LC/MS positive mode) m/z: 502 (M+H).

Compound 1o-1-3-3 Dimethylcarbamic acid3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-1-3was used instead of compound 1h-2-4 in step 2, and that dimethylaminewas used instead of methylamine in step 3.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.47 (3H, s), 2.76 (3H, s), 2.91 (3H,s), 2.94 (3H, s), 3.10 (3H, s), 3.96 (2H, s), 4.19 (2H, s), 6.98 (1H, d,J=8.1 Hz), 7.03-7.09 (2H, m), 7.23 (1H, m), 7.50 (1H, s), 8.02 (1H, s),9.85 (1H, br).

ESI (LC/MS positive mode) m/z: 537 (M+H).

Compound 1o-3-1-12-{3-[4-Methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}acetamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-3-1was used instead of compound 1h-2-4, and that ammonia was used insteadof methylamine.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 3.88 (2H, s), 4.00 (2H,s), 6.90-7.65 (9H, m).

ESI (LC/MS positive mode) m/z: 486 (M+H).

Compound 1o-3-1-2N-Methyl-2-{3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}acetamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-3-1was used instead of compound 1h-2-4.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 2.76-2.78 (1H, m), 3.88(2H, s), 4.00 (2H, s), 6.90-7.65 (9H, m).

ESI (LC/MS positive mode) m/z: 500 (M+H).

Compound 1o-3-4-22-{2-Fluoro-3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-3-4was used instead of compound 1h-2-4 in step 2.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.46 (3H, s), 2.60 (3H, d, J=4.6 Hz),3.97 (2H, s), 3.99 (2H, s), 6.92-7.07 (2H, m), 7.28-7.39 (4H, m), 7.50(1H, d, J=2.6 Hz), 7.95 (1H, d, J=8.7 Hz), 8.18 (1H, d, J=4.6 Hz).

ESI (LC/MS positive mode) m/z: 518 (M+H).

Compound 1o-3-1-3N,N-Dimethyl-2-{3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}acetamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1o-2-4-2, except that compound 1h-3-1was used instead of compound 1h-2-4, and that dimethylamine was usedinstead of methylamine.

¹H-NMR (CDCl₃, 270 MHz) δ (ppm): 2.46 (3H, s), 2.98 (3H, s), 3.04 (3H,s), 3.88 (2H, s), 4.00 (2H, s), 6.90-7.65 (9H, m).

ESI (LC/MS positive mode) m/z: 514 (M+H).

Compound 1j-1-6-4 Dimethylcarbamic acid3-(3-methanesulfonylamino-benzyl)-4,6-dimethyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-1-6 was used instead of compound 1h-2-16, and that methanesulfonicacid chloride was used instead of N-methylsulfamoyl chloride.

¹H-NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.22 (3H, s), 2.49 (3H, s), 2.89 (6H,s), 3.04 (3H, s), 3.95 (2H, s), 6.96 (1H, d, J=7.6 Hz), 7.00-7.08 (2H,m), 7.18-7.28 (2H, m), 7.75 (1H, s), 9.63 (1H, brs).

ESI (LC/MS positive mode) m/z: 445 (M+H).

Compound 1j-1-10-4 Dimethylcarbamic acid3-(2-methanesulfonylaminopyridin-4-ylmethyl)-4-methyl-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-2-16-2, except that compound1h-1-10 was used instead of compound 1h-2-16, and that methanesulfonicacid chloride was used instead of N-methylsulfamoyl chloride.

¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 10.73 (brs, 1H), 8.06 (d, 1H, J=5.1Hz), 7.87 (d, 1H, J=9.0 Hz), 7.26 (d, 1H, J=2.1 Hz), 7.19 (dd, 1H,J=8.7, 6.0 Hz), 6.85 (d, 1H, J=5.4 Hz), 6.78 (s, 1H), 3.96 (s, 2H), 3.20(s, 3H), 3.07 (s, 3H), 2.93 (s, 3H), 2.46 (s, 3H).

ESIMS m/z: 432 (M+H).

Compound 1j-1-3-4 CONH2 Dimethylcarbamic acid4-carbamoylmethyl-6-chloro-3-(3-(methanesulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Et₃N (13·L, 0.093 mmol) and methanesulfonyl chloride (3.6·L, 0.050 mmol)were added to a solution of dimethylcarbamic acid3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-ylester (20 mg, 0.047 mmol) in methylene chloride (1.0 mL), and themixture was stirred at room temperature for 2 hours. The solvent wasdistilled away by concentration under reduced pressure, and theresultant residue was purified by column chromatography to yield thetitle compound (5.0 mg, 22%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆+CD₃OD (1:4)) δ (ppm): 8.57 (s, 1H), 8.07 (s,1H), 7.90 (m, 1H), 7.82-7.74 (m, 3H), 4.74 (s, 2H), 4.64 (s, 2H), 3.86(s, 3H), 3.76 (s, 3H), 3.70 (s, 3H).

ESIMS m/z: 508 (M+H).

Compound 1j-1-3-4CONMe2 Dimethylcarbamic acid6-chloro-4-dimethylcarbamoylmethyl-3-(3-(methanesulfonyl)aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-4CONH2, except that compound7d-1-3CONMe2 was used instead of compound 7d-1-3CONH2

¹H NMR (270 MHz, CDCl₃) δ (ppm): 7.40 (s, 1H), 7.24-7.19 (m, 2H),7.07-7.00 (m, 3H), 3.97 (s, 2H), 3.80 (s, 2H), 3.16 (s, 3H), 3.12 (s,3H), 3.04 (s, 3H), 2.95 (s, 3H), 2.92 (s, 3H).

ESIMS m/z: 536 (M+H).

(General Processes-2 and -3)

Next, manufacturing examples associated with General processes-2 and -3previously mentioned will be explained.

Compound 2a-1 2-Fluoro-1-methyl-3-nitrobenzene

Cesium fluoride (97.5 g, 642 mmol) was added under nitrogen atmosphereto a solution of 2-chloro-1-methyl-3-nitrobenzene (73.4 g, 428 mmol) inDMSO (185 mL), and the mixture was stirred at 140° C. for 10 hours. Thereaction mixture was then poured into 0.5N hydrochloric acid andextracted twice with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate. A crude product wasobtained by vacuum concentration, and then purified by reduced-pressuredistillation (boiling point: 118° C. to 122° C./15 mm Hg) to yield thetitle compound (54.4 g, 82%) as a yellow oil.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 7.96 (m, 1H), 7.73 (m, 1H), 7.34 (t,J=8.2 Hz, 1H), 2.35 (d, J=2.4 Hz, 3H).

HPLC Rt=2.03 min.

HPLC conditions:

Column: Combi ODS (ODS, 5 μm, 4.6 mm T.D.×50 mm, Wako Pure ChemicalIndustries), COSMOSIL (ODS, 5 μm, 4.6 mm I.D.×50 mm, Nacalai Tesque),Intersil C18 (ODS, 5 μm, 4.6 mm I.D.×50 mm, GL Sciences), or SunFire C18(ODS, 5 μm, 4.6 mm I.D.×50 mm, Waters); Mobile phase: Water (A)containing 0.05% trifluoroacetic acid, and acetonitrile (B) containing0.05% trifluoroacetic acid;

Elution method: Stepwise solvent gradient elution (Solvent compositionwas changed from 10% B to 95% B in 3.5 minutes, then changed to 10% B in1 minute, and kept at 10% B for 0.5 minute);

Flow rate: 4.0 mL/min.

Compound 1a-1 1-Bromo methyl-2-fluoro-3-nitrobenzene

Benzoyl peroxide (10.7 g, 44 mmol) was added under reflux under nitrogenatmosphere to a solution of 2-fluoro-1-methyl-3-nitrobenzene (compound2a-1) (68.2 g, 440 mmol) and N-bromosuccinimide (95.0 g, 528 mmol) incarbon tetrachloride (1500 mL), and the mixture was stirred under refluxfor 5 hours. Impurities were then removed by filtration, and a crudeproduct was obtained by vacuum concentration. It was then purified bycolumn chromatography (hexane), and the title compound (68.7 g, 65%) wasobtained as a yellow to light brown oil.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.14 (dd, J=7.0, 1.6 Hz, 1H), 7.97(dd, J=6.5, 1.6 Hz, 1H), 7.46 (td, J=8.4, 1.4 Hz, 1H), 4.81 (d, J=1.4Hz, 2H).

HPLC Rt=2.25 min.

HPLC conditions were the same as those for the manufacturing example forcompound 2a-1.

Compound 3a-1 2-Chloro-3-nitrobenzoic acid methyl ester

Concentrated sulfuric acid (2.0 mL) was added to a solution of2-chloro-3-nitrobenzoic acid (10.0 g, 49.6 mmol) in methanol (80 mL),and the mixture was stirred under reflux overnight. After removingmethanol by vacuum concentration, water was added, and extraction wasperformed with ethyl acetate. The organic extract was washed in serieswith water, saturated sodium hydrogen carbonate and saturated saline,and dried over magnesium sulfate. The title compound (10.6 g, 99%) wasobtained by vacuum concentration as a white solid.

¹H NMR (CDCl₃) δ (ppm): 7.95 (dd, 1H), 7.84 (dd, 1H), 7.48 (t, 1H), 3.98(s, 3H).

HPLC Rt=11.88 min.

HPLC conditions:

Column: YMC-ODS A (150×6.0 mm);

Eluent: 0-20 min, MeCN/H₂O=10/90 to 100/0 (gradient), 20-30 min,MeCN/H₂O=100/0 (isocratic);

Flow rate: 1 mL/min.

Compound 2b-1 2-Fluoro-3-nitrobenzoic acid methyl ester

Cesium fluoride (11.2 g) was added to a solution of2-chloro-3-nitrobenzoic acid methyl ester (10.6 g, 49.0 mmol) in DMSO(49 mL), and the mixture was stirred at 140° C. for 40 minutes. Thereaction mixture was then poured into water and extracted with ethylacetate. The organic extract was washed in series with water andsaturated saline, and dried over magnesium sulfate. The title compound(9.23 g, 95%) was then obtained by vacuum concentration as a pale yellowsolid.

¹H NMR (CDCl₃) δ (ppm): 8.24-8.11 (m, 2H), 7.37 (t, 1H), 3.98 (s, 3H).

HPLC Rt=14.62 min.

HPLC conditions were the same as those for the manufacturing example forcompound 3a-1.

Compound 2c-1 (2-Fluoro-3-nitrophenyl)methanol

DIBAL (115.7 mL, 1.0 M in toluene) was added at −78° C. to a solution of2-fluoro-3-nitrobenzoic acid methyl ester (compound 2b-1) (9.22 g, 46.3mmol) in toluene (92 mL), and the reaction mixture was stirred at −78°C. for 30 minutes and at 0° C. for 30 minutes. The resultant reactionsolution was cooled again to −78° C., and methanol, aqueous saturatedRochelle salt solution and ethyl acetate were added thereto. Thereaction mixture was then stirred at room temperature for 1 hour, andextracted three times with ethyl acetate. The organic layer was washedwith saturated saline and dried over magnesium sulfate.

The title compound (7.52 g, 95%) was then obtained by vacuumconcentration as a brown oil.

¹H NMR (CDCl₃) δ (ppm): 7.95 (m, 1H), 7.84 (t, 1H), 7.31 (t, 1H), 4.87(s, 2H).

HPLC Rt=7.52 min.

HPLC conditions were the same as those for the manufacturing example forcompound 3a-1.

Compound 2c-2 4-Fluoro-3-nitrobenzyl alcohol

Sodium borohydride (1.36 g, 35.95 mmol) was added to a solution of4-fluoro-3-nitrobenzaldehyde (2.0 g, 11.83 mmol) in methanol (15 mL) andwater (3.0 mL), and the mixture was stirred at room temperature for 3hours. Water was then added to the reaction mixture, and extraction wasperformed with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate, and then concentratedunder reduced pressure to yield the title compound (2.10 g, 95%) as apale red oil.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 8.06 (dd, 1H, J=7.1, 2.2 Hz), 7.64 (m,1H), 7.28 (dd, 1H, J=10.7, 8.6 Hz), 4.76 (s, 2H).

Compound 1a-1 1-Bromomethyl-2-fluoro-3-nitrobenzene

A solution of phosphorus tribromide (4.8 mL) in anhydrous diethylether(100 mL) was added at 0° C. to a solution of(2-fluoro-3-nitrophenyl)methanol (compound 2c-1) (7.52 g, 46.3 mmol) inanhydrous diethylether (130 mL), and the mixture was stirred at 30minutes at 0° C. The reaction mixture was then poured into ice water andextracted with ethyl acetate. The organic extract was washed in serieswith saturated sodium hydrogen carbonate solution, water and saturatedsaline, and dried over magnesium sulfate. The title compound (7.10 g,70%) was then obtained as a brown oil.

¹H NMR (DMSO) δ (ppm): 8.14 (dd, J=7.0, 1.6 Hz, 1H), 7.97 (dd, J=6.5,1.6 Hz, 1H), 7.46 (td, J=8.4, 1.4 Hz, 1H), 4.81 (d, J=1.4 Hz, 2H).

HPLC Rt=2.25 min.

HPLC conditions were the same as those for the manufacturing example forcompound 2a-1.

Compound 1a-2 2-Bromomethyl-4-fluoro-3-nitrobenzene

Phosphorus tribromide (1.13 mL) was added to a solution of4-fluoro-3-nitrobenzyl alcohol (2.1 g, 11.23 mmol) in diethyl ether (40mL), and the mixture was stirred at room temperature for 1 hour. Waterwas then added to the reaction mixture, and extraction was performedwith ethyl acetate. The organic extract was washed with saturated sodiumhydrogen carbonate solution and saturated saline. After drying overmagnesium sulfate and concentrating under reduced pressure, theresultant residue was purified by column chromatography to yield thetitle compound (2.50 mg, 95%) as a pale yellow solid.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 8.10 (dd, 1H, J=7.1, 2.2 Hz), 7.67 (m,1H), 7.29 (dd, 1H, J=10.7, 8.6 Hz), 4.49 (s, 2H).

Compound 2c-73 (5-Nitro-thiophen-2-yl)methanol

NaBH₄ (248 mg, 6.55 mmol) was slowly added to a solution of(5-nitrothiophen-2-yl)aldehyde (1.03 g, 6.55 mmol) in methanol (10 mL)while cooling on ice. The temperature was raised to room temperature,and the mixture was stirred for 4 hours. A 1N HCl solution (20 mL) wasthen added thereto, and extraction was performed twice with ethylacetate (40 mL). The organic layer was then purified by silica gelchromatography (hexane:ethyl acetate=3:1) to yield the title compound(917 mg, 88%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.82 (1H, d, J=3.82Hz), 6.93 (1H, d, J=4.20 Hz), 4.88 (2H, s), 2.21 (1H, s).

Compound 1a-73 Methanesulfonic acid (5-nitro-thiophen-2-yl)methanolester

Methylene chloride (8.5 mL), triethylamine (0.90 mL, 6.42 mmol) andmethanesulfonic acid chloride (0.43 mL, 5.61 mmol) were mixed withcompound 2c-73 (851 mg, 5.35 mmol) at 0° C. The mixture was stirred at0° C. for 1 hour, and water (10 mL) was added thereto. The organic layerwas extracted with methylene chloride (10 mL), and the solvent wasdistilled away to yield the title compound (1.25 g, 98.5%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.84 (1H, d, J=4.20Hz), 7.13 (1H, d, J=4.20 Hz), 5.36 (2H, s), 3.06 (3H, s).

(General Process-4)

Next, manufacturing examples associated with General process-4previously mentioned will be explained.

Compound 4a-0-42-Oxo-2H-3-(2-fluoro-3-aminobenzyl)-4-methyl-7-hydroxy-1-benzopyran

Tin(II) chloride dihydrate (561 mg, 2.49 mmol) was added under nitrogenatmosphere to a solution of the starting material 1e-0-4 (150 mg, 0.46mmol) in ethyl acetate (4 mL), and heated under reflux for 1 hour.Saturated sodium hydrogen carbonate solution was then added to thereaction solution, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated saline and dried over anhydroussodium sulfate, and the solvent was distilled away under reducedpressure. The resultant residue was purified by silica gel columnchromatography (dichloromethane:methanol 30:1 to 10:1) to yield thetitle compound (91.8 mg, 88%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.35 (3H, s), 3.85 (2H, s), 5.06 (2H,br.s), 6.20 (1H, ddd, J=7.6, 1.5 Hz, J_(HF)=7.6 Hz), 6.59 (1H, ddd,J=8.2, 1.5 Hz, J_(HF)=8.2 Hz), 6.67-6.75 (2H, m), 6.81 (1H, dd, J=8.7,2.4 Hz), 7.64 (1H, d, J=2.4 Hz), 10.47 (1H, br.s).

ESI (LC/MS positive mode) m/z: 300 (M+H).

Compound 4a-0-52-Oxo-2H-3-(2-fluoro-3-aminobenzyl)-4-methyl-6-fluoro-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1e-0-5was used instead of compound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.32 (3H, s), 3.84 (2H, s), 6.20 (1H,dd, J=7.1, 7.1 Hz), 6.58-6.87 (3H, m), 7.55 (1H, d, J=11.0 Hz).

ESI (LC/MS positive mode) m/z: 318 (M+H).

Compound 4a-0-12-Oxo-2H-3-(3-aminobenzyl)-4-methyl-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1e-0-1was used instead of compound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.36 (3H, s), 3.32 (2H, brs), 3.75(2H, s), 4.96 (1H, brs), 6.32-6.43 (3H, m), 6.71 (1H, d, J=2.4 Hz), 6.81(1H, dd, J=2.4, 8.7 Hz), 6.89 (1H, ddd, J=2.1, 7.3, 7.3 Hz), 7.64 (1H,d, J=8.7 Hz).

ESI (LC/MS positive mode) m/z: 282 (M+H).

Compound 4a-0-32-Oxo-2H-3-(3-aminobenzyl)-4-methyl-6-chloro-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1e-0-3was used instead of compound 1e-0-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.36 (3H, s), 3.32 (2H, brs), 3.79(2H, s), 4.93 (1H, brs), 6.29-6.43 (3H, m), 6.82-6.93 (2H, m), 7.79 (1H,s).

ESI (LC/MS positive mode) m/z: 316 (M+H).

Compound 4a-0-63-(2-Methyl-3-aminobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1e-0-6was used instead of compound 1e-0-4.

¹H NMR (Bruker, 300 MHz, DMSO-d₅) δ (ppm): 10.49 (1H, s), 7,63 (1H, d,J=8.8 Hz), 6.82 (1H, dd, J=2.3, 8.8 Hz), 6.72-6.68 (2H, m), 6.48 (1H, d,J=7.6 Hz), 5.99 (1H, d, J=7.6 Hz), 4.77 (2H, s), 3.79 (2H, s), 2.25 (3H,s), 2.07 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 295.95 (M+H).

Compound 4a-0-453-(2-Aminobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

10% Pd/C (15 mg, 20 w/w %) was added to a methanol solution (1 mL) ofcompound 1e-0-45 (75 mg, 2.4 mmol), and the mixture was stirred for 1hour under molecular hydrogen atmosphere at 1 atmosphere. The Pd/C wasremoved by filtration, and the filtrate was purified by silica gelchromatography (methylene chloride:methanol=10:1) to yield the titlecompound (25 mg, 37%).

¹H-NMR (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 10.44 (1H, s), 7.64 (1H, d,J=8.8 Hz), 6.88 (1H, t, J=7.4 Hz), 6.82 (1H, dd, J=2.3, 8.8 Hz), 6.73(1H, d, J=1.9 Hz), 6.65 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=7.6 Hz), 6.41(1H, t, 7.6 Hz), 5.00 (2H, s), 3.65 (2H, s), 2.36 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 281.84 (M+H).

Compound 4a-0-463-(4-Aminobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1e-0-46was used instead of compound 1e-0-4.

¹H-NMR. (Bruker, 300 MHz, DMSO-d₆) δ (ppm): 10.44 (1H, s), 7.61 (1H, d,J=8.8 Hz), 6.85 (2H, d, J=8.4 Hz), 6.79 (1H, dd, J=2.3, 8.8 Hz), 6.68(1H, d, J=2.3 Hz), 6.45 (2H, d, J=8.4 Hz), 4.84 (2H, s), 3.72 (2H, s),2.37 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 281.65 (M+H).

Compound 4a-0-513-(3-Aminophenylamino)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 4a-0-51was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.37 (s, 1H), 7.59 (d, 1H, J=8.9Hz), 7.02 (s, 1H), 6.84 (dd, 1H, J=8.6, 2.3 Hz), 6.80-6.73 (m, 3H),5.98-5.88 (m, 2H), 5.80 (m, 1H), 5.05 (brs, 1H), 2.22 (s, 3H).

ESIMS m/z: 283 (M+H).

Compound 4a-0-733-(5-Nitro-thiophen-2-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

A mixture of compound 1e-0-73 (30 mg, 0.095 mmol) with acetic acid (0.15mL) was then combined with a mixture of tin(II) chloride dihydrate (129mg, 0.57 mmol) and concentrated hydrochloric acid (0.25 mL) at roomtemperature, and the obtained mixture was stirred for 2 hours. Water (10mL) was added, the mixture was stirred for 10 minutes, and then asaturated NaHCO₄ solution was added to adjust the pH of the reactionmixture to 10. The organic layer was extracted twice with a mixedsolvent of methylene chloride and methanol (5:1) (20 mL). It was thenpurified by silica gel chromatography (hexane:ethyl acetate=1:3) toyield the title compound (5 mg, 18%).

¹H-NMR (Bruker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 10.36 (1H, s), 7.63(1H, d, J=8.77 Hz), 6.97 (1H, dd, J=8.77, 2.30 Hz), 6.69 (1H, d, J=2.30Hz), 6.30 (1H, d, J=3.43 Hz), 5.63 (1H, d, J=3.43 Hz), 5.17 (2H, s),3.82 (2H, s), 2.40 (3H, s).

MS (Micromass, Quattromicro, ESI+) m/z: 288.03 (M+1).

Compound 1h-2-44-Methyl-3-(2-fluoro-3-aminobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

(Synthesis Scheme 2)

60% sodium hydride (11.5 mg, 0.28 mmol) was added under nitrogenatmosphere to a solution of the starting material 4a-0-4 (90.6 mg, 0.30mmol) in N,N-dimethylformamide (2 mL), and the mixture was stirred atroom temperature for 1 hour. 2-Bromopyrimidine (48 mg, 0.30 mmol) wasthen added thereto, and the mixture was stirred at 100° C. for 5 hours.Ethyl acetate was then added to the reaction solution, and the solutionwas washed with sodium hydrogen carbonate solution, water and saturatedsaline. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was distilled away under reduced pressure. The resultantresidue was purified by silica gel column chromatography(dichloromethane:methanol=1:0 to 40:1) to yield the title compound (60.5mg, 56%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.45 (3H, s), 3.93 (2H, s), 5.08 (2H,br.s), 6.25 (1H, ddd, J=7.2, 1.7 Hz, J_(HF)=7.2 Hz), 6.61 (1H, ddd,J=8.2, 1.7 Hz, J_(HF)=8.2 Hz), 6.73 (1H, dd, J=8.2, 7.2 Hz), 7.26 (1H,dd, J=8.8, 2.4 Hz), 7.34 (1H, t, J=4.8 Hz), 7.37 (1H, d, J=2.4 Hz), 7.89(1H, d, J=8.8 Hz), 8.68 (2H, d, J=4.8 Hz).

ESI (LC/MS positive mode) m/z: 378 (M+H).

Compound 1h-3-44-Methyl-3-(2-fluoro-3-aminobenzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

(Synthesis Scheme 2)

The starting material 4a-0-4 (5.0 g, 16.9 mmol) was dissolved inN,N-dimethylformamide (75 mL), and 2-bromothiazole (6.0 mL, 67.6 mmol)and cesium carbonate (11.0 g, 33.8 mmol) were added thereto. The mixturewas stirred at 100° C. for 19 hours. Ethyl acetate was then added to thereaction solution, and the solution was washed with water and saturatedsaline. The organic layer was dried over anhydrous magnesium sulfate,and the solvent was distilled away under reduced pressure. The resultantresidue was purified by silica gel column chromatography(dichloromethane:methanol=50:1) to yield the title compound (2.4 g, 38%)as a pale yellow powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.44 (3H, s), 3.92 (2H, s), 6.24 (1H,ddd, J=1.5, 7.0 Hz, J_(HF)=7.0 Hz), 6.61 (1H, ddd, J=1.5, 8.3 Hz,J_(HF)=8.3 Hz), 6.72 (1H, dd, J=7.0, 8.3 Hz), 7.34-7.38 (4H, m), 7.49(1H, d, J=2.5 Hz), 7.92 (1H, d, J=8.9 Hz).

ESI (LC/MS positive mode) m/z: 383 (M+H).

(General Process-5)

Next, manufacturing examples associated with General process-5previously mentioned will be explained.

Compound 5b-0-13 2-(Di-tert-butyloxycarbonyl)amino-6-methylpyridine

2-Amino-6-methylpyridine (15 g, 138.7 mmol) and Boc₂O (41.4 mL, 180.3mmol) were stirred at 60° C. overnight, and 100 mL of THF was then addedthereto at room temperature. The reaction solution was added dropwise toa mixed solution of Boc₂O (95.6 mL, 416.1 mmol) and DMAP (59.3 g, 485.5mmol), and the mixture was stirred at room temperature for 4 hours.Ethyl acetate was then added to the reaction solution, and the solutionwas washed with ammonium chloride solution, sodium hydrogen carbonatesolution and saturated saline. The organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled away underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography to yield the title compound (34.8 g, 82%) as awhite solid.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 1.31-1.39 (18H, m), 2.42 (3H, s), 7.14(1H, d, J=7.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.74 (1H, dd, J=7.6 Hz).

ESI (LC/MS positive mode) m/z: 309 (M+H).

Compound 5c-0-132-(Di-tert-butyloxycarbonyl)amino-6-(bromomethyl)pyridine

Under nitrogen atmosphere, 6-(di-t-butoxycarbonyl)amino-2-methylpyridine(compound 5b-0-13) (6.0 g, 19.5 mmol), N-bromosuccinimide (4.5 g, 25.3mmol) and benzoyl peroxide (675 mg, 1.95 mmol) were stirred at 80° C.for 4 hours. The reaction solution was then filtered, and the solventwas distilled away under reduced pressure. The resultant residue waspurified by silica gel column chromatography to yield the title compound(4.34 g).

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 1.31-1.39 (18H, m), 4.51 (2H, s), 7.20(1H, d, J=8.1 Hz), 7.31 (1H, d, J=8.1 Hz), 7.73 (1H, dd, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 388 (M+H).

Compound 5t-0-102-(2-(Di-tert-butyloxycarbonyl)aminopyridin-4-ylmethyl)-3-oxobutyricacid ethyl ester

Ethyl acetoacetate (109.6 μL, 0.86 mmol) was dissolved in THF (2.0 mL),and 2-(di-t-butoxycarbonyl)amino-4-(bromomethyl)pyridine (which had beenobtained by the method described in Bioorganic & Medicinal ChemistryLetters 2004, 14, 2227-2231) and NaH (39.0 mg, 0.97 mmol) were addedthereto. The mixture was stirred at room temperature for 12 hours. Waterwas then added to the reaction solution, and the solution was extractedwith ethyl acetate. After washing with sodium hydrogen carbonatesolution and saturated saline, the organic layer was dried overanhydrous magnesium sulfate, and the solvent was distilled away underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography to yield the title compound (206.2 mg, 83%).

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 1.22 (3H, t, J=6.7 Hz), 1.31-1.39 (18H,m), 2.23 (3H, s), 3.17 (1H, dd, J=8.1, 5.4 Hz), 3.78 (1H, dd, J=8.1 Hz),4.10-4.22 (2H, m), 7.02 (1H, d, J=5.4 Hz), 7.05 (1H, brs), 8.37 (1H, d,J=5.4 Hz).

ESI (LC/MS positive mode) m/z: 437 (M+H).

Compound 5t-0-132-(2-(Di-tert-butyloxycarbonyl)aminopyridin-6-ylmethyl)-3-oxobutyricacid ethyl ester

The title compound was obtained under the same conditions as in themanufacturing example for compound 5t-0-10, except that compound 5c-0-13was used instead of2-(di-t-butoxycarbonyl)amino-4-(bromomethyl)pyridine.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 1.22 (3H, t, J=6.7 Hz), 1.31-1.39 (18H,m), 3.20-3.44 (2H, m), 4.11-4.28 (3H, m), 7.06 (1H, d, J=8.1 Hz), 7.10(1H, d, J=8.1 Hz), 7.63 (1H, dd, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 437 (M+H).

Compound 5d-0-123-(2-Aminopyridin-4-ylmethyl)-6-chloro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Compound 5t-0-10 (180.9 mg, 414 μmol) and 4-chlororesorcinol (71.9 mg,497.3 μmol) were stirred in concentrated sulfuric acid (66.3 μL, 1.24mmol) at room temperature for 24 hours. Ethyl acetate was then added tothe reaction solution, and the solution was washed with sodium hydrogencarbonate solution and saturated saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was distilled awayunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (methylene chloride:methanol=5:1) to yield thetitle compound (28.0 mg).

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 2.36 (3H, s), 3.87 (2H, s), 6.41 (1H,brs), 6.51 (1H, d, J=5.4 Hz), 6.69 (1H, s), 7.66 (1H, s), 7.75 (1H, d,J=5.4 Hz).

ESI (LC/MS positive mode) m/z: 317 (M+H).

Compound 5d-0-103-(2-Aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-10 and resorcinolunder the same conditions as in the manufacturing example for compound5d-0-12.

¹H NMR (300 MHz) (DMSO-d₆) δ (ppm): 2.35 (3H, s), 3.76 (2H, s), 5.76(2H, brs), 6.20 (1H, s), 6.35 (1H, d, J=5.34 Hz), 6.72 (1H, d, J=2.29Hz), 6.82 (1H, dd, J=2.67, 8.77 Hz), 7.65 (1H, d, J=8.77 Hz), 7.75 (1H,d, J=5.34 Hz), 10.46 (1H, brs).

Mass (Micromass, Quattromicro) (ESI+) m/z: 282.87 (M+H).

Compound 5d-0-113-(2-Aminopyridin-4-ylmethyl)-6-fluoro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-10 and4-fluororesorcinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (300 MHz) (DMSO-d₆) δ (ppm): 2.35 (3H, s), 3.76 (2H, s), 5.74(2H, brs), 6.19 (1H, s), 6.34 (1H, d, J=5.72 Hz), 6.90 (1H, d, J=7.63Hz), 6.64 (1H, d, J=11.83 Hz), 7.75 (1H, d, J=5.34 Hz), 11.02 (1H, brs).

Compound 5d-0-133-(2-Aminopyridin-6-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-13 and resorcinolunder the same conditions as in the manufacturing example for compound5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.42 (3H, s), 3.82 (2H, s), 5.75-5.85(2H, m), 6.10-6.20 (2H, m), 6.70 (1H, brs), 6.78 (1H, d, J=8.1 Hz), 7.23(1H, dd, J=8.1 Hz), 7.64 (1H, d, J=8.1 Hz).

ESI (LC/MS positive mode) m/z: 283 (M+H).

Compound 5d-0-143-(2-Aminopyridin-6-ylmethyl)-6-fluoro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-13 and4-fluororesorcinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.38 (3H, s), 3.82 (2H, s), 5.78 (2H,brs), 6.22 (1H, d, J=7.6 Hz), 6.25 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=7.5Hz), 7.23 (1H, t, J=7.6 Hz), 7.62 (1H, d, J=11.9 Hz), 11.0 (1H, brs).

ESI (LC/MS positive mode) m/z: 301 (M+H).

Compound 5d-0-153-(2-Aminopyridin-6-ylmethyl)-6-chloro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-13 and4-chlororesorcinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.38 (3H, s), 3.82 (2H, s), 5.80 (2H,brs), 6.24 (1H, d, J=7.6 Hz), 6.27 (1H, d, J=7.6 Hz), 6.89 (1H, s), 7.23(1H, t, J=7.6 Hz), 7.78 (1H, s).

ESI (LC/MS positive mode) m/z: 317 (M+H).

Compound 5d-0-163-(3-Fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-16a andresorsinol under the same conditions as in the manufacturing example forcompound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.37 (3H, s), 3.86 (2H, s), 6.16 (2H,brs), 6.23 (1H, dd, J=5.1 Hz), 6.91 (1H, s), 7.60 (1H, d, J=5.1 Hz),7.85 (1H, s).

ESI (LC/MS positive mode) m/z: 301 (M+H).

Compound 5d-0-17

3-(3-Fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-16a and4-fluororesorsinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.36 (3H, s), 3.86 (2H, s), 6.10 (2H,br), 6.23 (1H, dd, 5.1 Hz), 6.89 (1H, d, J=6.6 Hz), 7.57 (1H, d, J=5.1Hz), 7.65 (1H, d, J=12 Hz).

ESI (LC/MS positive mode) m/z: 319 (M+H).

Compound 5d-0-183-(3-Fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-6-chloro-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-16a and4-chlororesorsinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.40 (3H, s), 3.86 (2H, s), 6.36 (1H,dd, J=5.1 Hz), 6.91 (1H, s), 7.60 (1H, d, J=5.1 Hz), 7.85 (1H, s).

ESI (LC/MS positive mode) m/z: 335 (M+H).

Compound 5d-0-193-(3-Fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-16a and4-methylresorsinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 2.19 (3H, s), 2.37 (3H, s), 3.85 (2H,s), 6.09 (2H, brs), 6.21 (1H, dd, J=5.1 Hz), 6.71 (1H, s), 7.54 (1H, s),7.56 (1H, d, J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 315 (M+H).

Compound 5d-0-19Me3-(2-Amino-3-fluoropyridin-4-ylmethyl)-4-ethyl-7-hydroxy-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-16Meb and4-methylresorsinol under the same conditions as in the manufacturingexample for compound 5d-0-12.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.06 (2H, t, J=7.4 Hz), 2.20 (3H, s),2.79 (2H, brq, J=7.4 Hz), 3.83 (2H, s), 6.10 (2H, s), 6.20 (1H, t, J=5.1Hz), 6.75 (1H, s), 7.55 (1H, s), 7.57 (1H, d, J=5.1 Hz), 10.50 (1H, s).

ESI (LC/MS positive mode) m/z: 329 (M+H).

Compound 5d-0-4S13-(2-Fluoro-3-aminobenzyl)-7-mercapto-4-methyl-2-oxo-2H-1-benzopyran

152 mg (1.21 mmol) of 3-hydroxy-benzenethiol and 153 mg (0.60 mmol) of2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester were added topolyphosphoric acid (6 g), and the mixture was stirred and heated at 70°C. for 2.5 hours. Water was then added to the reaction mixture, and theprecipitated solid was filtered out. The obtained solid was purified bysilica gel column chromatography (dichloromethane:methanol=50:1 to 20:1)to yield 12 mg (1%) of compound 5d-0-4S1 as a pale yellow powder.

ESI (LC-MS positive mode) m/z: 316 (M+H).

Compound 5d-7-4S23-(2-Fluoro-3-aminobenzyl)-7-methyloxy-4-methyl-2-oxo-2H-1-benzothiopyran

The title compound was synthesized using 3-methyloxy-benzenethiol and2-(2-fluoro-3-aminobenzyl)-3-oxobutanoic acid ethyl ester under the sameconditions as in the manufacturing example for compound 5d-0-4S1.

¹H-NMR (270 MHz, CDCl₃) δ (ppm): 2.46 (3H, s), 3.70 (2H, brs), 3.88 (3H,s), 4.12 (2H, s), 6.39 (1H, ddd, J=8.1, 1.3 Hz, J_(HF)=8.1 Hz), 6.61(1H, ddd, J=8.2, 1.4 Hz, J_(HF)=8.2 Hz), 6.77 (1H, dd, J=7.9, 7.9 Hz),6.91 (1H, d, J=2.6 Hz), 6.96 (1H, dd, J=9.1, 2.6 Hz), 7.80 (1H, d, J=9.1Hz).

ESI (LC-MS positive mode) m/z: 330 (M+H).

Compound 5d-0-4S23-(2-Fluoro-3-aminobenzyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzothiopyran

13.5 mg (0.041 mmol) of compound 5d-7-4S2 was dissolved indichloromethane (1 mL), and 410 μL (0.41 mmol) of a 1 mol/L borontribromide dichloromethane solution was added thereto. The mixture wasstirred under nitrogen atmosphere for 18 hours. Water was then added tothe reaction mixture, and the precipitated solid was filtered of toyield 7.6 mg (59%) of compound 5d-0-4S2 as a white powder.

¹H-NMR (270 MHz, DMSO-d₆) δ (ppm): 2.42 (3H, s), 3.95 (2H, s), 5.61 (2H,brs), 6.07 (1H, ddd, J=7.2, 1.1 Hz, J_(HF)=7.2 Hz), 6.58 (1H, ddd,J=8.2, 1.2 Hz, J_(HF)=8.2 Hz), 6.69 (1H, dd, J=8.2, 7.2 Hz), 6.80-6.62(2H, m), 7.91 (1H, d, J=9.7 Hz).

ESI (LC-MS positive mode) m/z: 316 (M+H).

Compound 5c-0-53 N-(3-Mercaptophenyl)acetamide

3-Aminothiophenol (1.0 g, 7.99 mmol), acetic anhydride (0.83 mL) andtriethyl amine (1.7 mL) were dissolved in methylene chloride, and thesolution was stirred at room temperature for 2 hours. It was thenpurified by silica gel chromatography (hexane:ethyl acetate=3:1) toyield the title compound (1.16 g, 87%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 7.18 (1H, t, J=7.6 Hz), 6.80 (1H, d,J=7.6 Hz), 6.75 (1H, m), 6.71 (1H, dd, J=2.3, 8.0 Hz), 3.72 (2H, bs),2.40 (3H, s).

MS (ESI+) m/z: 167.91 (M+H).

Compound 5t-0-53 2-(3-Acetoamino-thiophenoxy)-3-oxobutyric acid ethylester

Compound 5c-0-53 (600 mg, 3.59 mmol) and 2-chloro-3-oxobutyric acidethyl ester (0.50 mL) were dissolved in methylene chloride (6 mL), andtriethylamine (0.52 mL) was slowly added dropwise thereto at 0° C. Themixture was raised to room temperature and stirred overnight. It wasthen purified by silica gel chromatography (hexane:ethyl acetate=5:1) toyield the title compound (181 mg, 17%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 11.8 (1H, s), 7.24 (1H, m), 7.01 (1H,m), 6.87 (2H, m), 4.1 (3H, m), 2.27 (6H, s), 1.18 (3H, m).

MS (ESI+) m/z: 294.99 (M).

Compound 5d-0-533-(3-Amino-thiophenoxy)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Compound 5t-0-53 (163 mg, 0.552 mmol) and resorcinol (61 mg) were mixedwith 70% sulfuric acid (0.5 mL) while cooling on ice, and the mixturewas raised to room temperature and stirred overnight. The reactionmixture was added to ice water, and the obtained solid was filtered outto yield the title compound (149 mg, 90%).

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 10.7 (1H, s), 7.74 (1H, d, J=8.8 Hz),6.93 (1H, t, J=8.0 Hz), 6.86 (1H, dd, J=2.3, 8.4 Hz), 6.74 (1H, d, J=2.3Hz), 6.37 (3H, m), 5.59 (2H, bs), 2.66 (3H, s).

MS (ESI+) m/z: 300.08 (M+H).

Compound 5t-0-52 2-(3-Acetoaminophenoxy)-3-oxobutyric acid ethyl ester

A solution of 3-acetylaminophenol (1 g, 6.61 mmol) in tetrahydrofuran(3.3 mL) was added to a mixture of NaH (264 mg) with tetrahydrofuran(2.6 mL) at 0° C. The mixture was stirred at room temperature for 1hour, and tetramethylenediamine (1.0 mL) and 2-chloro-3-oxobutyric acidethyl ester (1.0 mL) were then added thereto. The mixture was heatedunder reflux for 8 hours, and purified by silica gel chromatography(methylene chloride:methanol=50:1) to yield the title compound (210 mg,11%).

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 7.34 (1H, s), 7.29 (1H, s), 7.21 (2H,m), 7.04 (1H, d, J=7.6 Hz), 6.65 (1H, dd, J=2.3, 8.4 Hz), 5.09 (1H, s),4.29 (2H, q, J-7.2 Hz), 2.38 (3H, s), 2.16 (3H, s), 1.29 (3H, t, J=6.9Hz).

MS (ESI+) m/z: 280.05 (M+H).

Compound 5d-0-52P3-(3-Acetylamino-phenoxy)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-52 and resorcinolunder the same conditions as in the manufacturing example for compound5d-0-53.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 10.5 (1H, s), 9.91 (1H, s), 7.66 (1H,d, J=8.8 Hz), 7.23 (3H, m), 6.89 (1H, dd, J=2.3, 8.8 Hz), 6.79 (1H, d,J=2.3 Hz), 6.66 (1H, m), 2.29 (3H, s), 1.99 (3H, s).

MS (EST+) m/z: 326.02 (M+H).

Compound 5d-0-523-(3-Aminophenoxy)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-52 and resorcinolunder the same conditions as in the manufacturing example for compound5d-0-53.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 7.61 (1H, m), 6.91 (1H, m), 6.85 (1H,m), 6.74 (1H, m), 6.21 (1H, J=8.4 Hz), 6.08 (2H, m), 5.12 (2H, bs), 2.26(3H, s).

MS (ESI+) m/z: 283.97 (M+H).

Compound 5t-0-74 2-(2-Acetylamino-thiazol-4-ylmethyl)-3-oxobutanoic acidethyl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1c-2, except that2-acetylamino-4-chloromethyl-thiazole was used instead of1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H-NMR (Bruker (ARX-300), CDCl₃) δ (ppm): 9.42 (1H, s), 9.60 (1H, s),4.21-4.14 (2H, m), 3.94 (1H, t, J=7.4 Hz), 3.19 (2H, q), 2.24 (3H, s),2.23 (3H, s), 1.23 (3H, t, J=7.1 Hz).

Compound 5d-0-74P3-(2-Acetylamino-thiazol-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-74 under the sameconditions as in the manufacturing example for compound 5d-0-12. It wasisolated by silica gel chromatography as a separate fraction of compound5d-0-74.

¹H-NMR (Bruker (ARX-300), DMSO-d₆) δ (ppm): 11.97 (1H, s), 10.42 (1H,s), 7.42 (1H, d, J=8.4), 6.80 (1H, dd, J=9.0, 2.4 Hz), 6.72 (1H, s),6.70 (1H, d, J=2.7 Hz), 3.90 (2H, s), 2.38 (3H, s), 2.08 (3H, s).

Compound 5d-0-743-(2-Aminothiazol-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized using compound 5t-0-74 under the sameconditions as in the manufacturing example for compound 5d-0-12. It wasisolated by silica gel chromatography as a separate fraction of compound5d-0-74P.

¹H-NMR (Bruker (ARX-300), CDCl₃) δ (ppm): 10.40 (1H, s), 7.63 (1H, d,J=9.0 Hz), 6.81 (2H, s), 6.79 (1H, dd, J=9.3, 2.7 Hz), 6.69 (1H, d,J=2.1 Hz), 6.04 (1H, s), 3.71 (2H, s), 2.38 (3H, s).

(General Process-6)

Next, manufacturing examples associated with General process-6previously mentioned will be explained.

Compound 6b-1-4 Dimethylcarbamic acid4-bromomethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

THF (0.9 mL) was added to dimethylcarbamic acid3-(2-fluoro-3-nitrobenzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester(compound 1g-1-4) (47.6 mg), and the resultant suspension was stirred at−78° C. for 20 minutes to yield a dark brown solution. This solution wasadded at 0° C. to a solution of N-bromosuccinimide (28 mg) in THF (0.8mL) (which had been prepared in advance in a separate container), andthe mixture was stirred at 0° C. for 40 minutes. This reaction solutionwas poured into 1N hydrochloric acid (0.119 mL) diluted with ice water(20 mL), and then extracted with ethyl acetate. The organic layerextraction liquid was washed with saturated saline, and the organiclayer was dried over anhydrous magnesium sulfate. The solvent wasdistilled away under reduced pressure, and the resultant residue waspurified by thin layer silica gel chromatography (hexane:ethylacetate=1:1) to yield the title compound (24.3 mg).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.04 (3H, s), 3.13 (3H, s), 4.15 (2H,s), 4.62 (2H, s), 7.11-7.35 (3H, m), 7.62-7.76 (1H, m), 7.65 (1H, ddd,J=9.0, 8.2, 1.8 Hz), 7.71 (1H, d, J=9.5 Hz), 7.92 (1H, ddd, J=9.0, 8.2,1.8 Hz).

ESI (LC/MS positive mode) m/z: 479 (M), 481 (M+2H).

Compound 6b-1-1 Dimethylcarbamic acid4-bromomethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6b-1-4, except that compound 1g-1-1was used instead of compound 1g-1-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.94 (3H, s), 3.07 (3H, s), 4.20 (2H,s), 5.07 (2H, s), 7.25 (1H, dd, J=8.7, 2.3 Hz), 7.30 (1H, d, J=2.3 Hz),7.58 (1H, t, J=8.1 Hz), 7.77 (1H, brd, J=8.1 Hz), 7.96 (1H, d, J=8.7Hz), 8.05-8.13 (1H, m), 8.22 (1H, t, J=1.9 Hz).

ESI (LC/MS positive mode) m/z: 502 (M+acetonitrile), 504(M+acetonitrile+2H).

Compound 6b-1-2 Dimethylcarbamic acid4-bromomethyl-6-fluoro-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6b-1-4, except that compound 1g-1-2was used instead of compound 1g-1-4.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.05 (3H, s), 3.15 (3H, s), 4.18 (2H,s), 4.50 (2H, s), 7.45-7.55 (2H, m), 7.66 (1H, d, J=8.1 Hz), 8.05-8.20(2H, m).

One of the proton peaks of the benzene ring was overlapped with theCDCl₃ peak.

ESI (LC/MS positive mode) m/z: 479 (M), 481 (M+2H).

Compound 6b-1-3 Dimethylcarbamic acid6-chloro-4-bromomethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6b-1-4, except that compound 1g-1-3was used instead of compound 1g-1-4.

¹H NMR (DMSO-d₅, 270 MHz) δ (ppm): 8.22 (s, 1H), 8.15 (s, 1H), 8.09 (d,J=8.1 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.50 (s,1H), 5.11 (s, 2H), 4.21 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 497 (M+H).

Compound 6b-2-44-Bromomethyl-3-(2-fluoro-3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6b-1-4, except that compound 1g-2-4was used instead of compound 1g-1-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.70 (d, J=4.9 Hz, 2H), 8.05-8.00 (m,2H), 7.63 (t, J=6.4 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.40-7.30 (m, 3H),5.03 (s, 2H), 4.16 (s, 2H).

ESIMS m/z: 486 (M+H).

Compound 6c-1-4 Dimethylcarbamic acid4-fluoromethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Acetonitrile (1.0 mL) was added to dimethylcarbamic acid4-bromomethyl-3-(2-fluoro-3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester (compound 6b-1-4) (24.0 mg), and potassium fluoride (3.1 mg) and18-crown-6 (13.2 mg) were added to the resultant suspension whilestirring at room temperature. The mixture was stirred at 60° C. for 4hours, potassium fluoride (3.1 mg) and 18-crown-6 (13.2 mg) were thenadded to the reaction solution, and the mixture was further stirred at60° C. for 1.5 hours. This reaction solution was poured into 1Nhydrochloric acid (0.110 mL) diluted with ice water (20 mL), and thenextracted with ethyl acetate. The resultant organic layer extractionliquid was washed with saturated saline, and the organic layer was driedover anhydrous magnesium sulfate. The solvent was distilled away underreduced pressure, and the resultant residue was purified by thin layersilica gel chromatography (hexane:ethyl acetate=1:1) to yield the titlecompound (14.7 mg).

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.03 (3H, s), 3.13 (3H, s), 4.17 (2H,s), 5.75 (2H, d, J=46.8 Hz), 7.11-7.20 (2H, m), 7.22 (1H, td, J=8.2, 1.3Hz), 7.70 (1H, td, J=8.2, 1.4 Hz), 7.78 (1H, dt, J=7.4, 1.8 Hz), 7.92(1H, ddd, J=8.2, 6.8, 1.4 Hz).

ESI (LC/MS positive mode) m/z: 419 (M+H).

Compound 6c-1-1 Dimethylcarbamic acid4-fluoromethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6c-1-4, except that compound 6b-1-1was used instead of compound 6b-1-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 2.93 (3H, s), 3.07 (3H, s), 4.07 (2H,brs), 5.88 (2H, d, J=46.3 Hz), 7.23 (1H, dd, J=8.7, 2.3 Hz), 7.30 (1H,d, J=2.3 Hz), 7.58 (1H, t, J=8.1 Hz), 7.73 (1H, d, J=8.7 Hz), 7.93 (1H,dd, J=8.1, 1.8 Hz), 8.02-8.12 (1H, in), 8.15 (1H, t, J=1.8 Hz).

ESI (LC/MS positive mode) m/z: 401 (M+H).

Compound 6c-1-2 Dimethylcarbamic acid6-fluoro-4-fluoromethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6c-1-4, except that compound 6b-1-2was used instead of compound 6b-1-4.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 3.05 (3H, s), 3.15 (314, s), 4.21 (2H,brs), 5.65 (2H, d, J=46.8 Hz), 7.45-7.65 (3H, m), 8.05-8.18 (2H, m).

One of the proton peaks of the benzene ring was overlapped with theCDCl₃ peak.

ESI (LC/MS positive mode) m/z: 419 (M+H).

Compound 6c-1-3 Dimethylcarbamic acid6-chloro-4-fluoromethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6c-1-4, except that compound 6b-1-3was used instead of compound 6b-1-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.12 (s, 1H), 8.09 (s+d, 2H), 7.72(d, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.56 (s, 1H), 5.95 (d, J=46.0Hz, 2H), 4.22 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 435 (M+H).

Compound 6c-2-44-Fluoromethyl-3-(2-fluoro-3-nitrobenzyl)-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 6c-1-4, except that compound 6b-2-4was used instead of compound 6b-1-4.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.68 (d, J=4.9 Hz, 2H), 8.02-7.96 (m,2H), 7.62 (t, J=6.5 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.35-7.29 (m, 3H),5.91 (d, J=46.2 Hz, 2H), 4.18 (s, 2H).

ESIMS m/z: 426 (M+H).

Compound 6a-3-4-1P3-(2-Fluoro-3-{[1-phenyl-meth-(Z)-ylidene]-amino}-benzyl-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

Methanol (4.0 mL) was added to3-(3-amino-2-fluorobenzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran(compound 1h-3-4) (200 mg), and benzaldehyde (0.053 mL) was added to theresultant suspension while stirring at room temperature. The suspensionwas heated under reflux for 3 hours. The reaction solution was thencooled to room temperature, and the solvent was distilled away underreduced pressure. The resultant residue was purified by silica gelchromatography (amino gel) (dichloromethane) to yield the title compound(233 mg).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 4.04 (2H, s), 6.92-7.20 (3H, m),7.31-7.40 (4H, m), 7.45-7.60 (4H, m), 7.91-8.00 (3H, m), 8.66 (1H, s).

The CH₃ peak was overlapped with the DMSO peak.

Compound 6b-3-4-1P4-Bromomethyl-3-(2-fluoro-3-{[phenyl-meth-(Z)-ylidene]-amino}-benzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

THF (4.5 mL) was added to3-(2-fluoro-3-{[1-phenyl-meth-(Z)-ylidene]-amino}-benzyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran(compound 6a-3-4-1P) (226 mg), and the mixed solution was stirred at−78° C. for 20 minutes, and further stirred at 0° C. for 1 hour to yielda dark brown solution. This solution was added over 10 minutes to asolution of N-bromosuccinimide (178 mg) in THF (3.0 mL) (which had beenprepared in advance in a separate container), and the mixture wasfurther stirred at 0° C. for 1 hour. The reaction solution was added towater (5 mL) to complete the reaction, and the solution was extractedwith ethyl acetate. The resultant organic layer extraction liquid waswashed with saturated saline, and the organic layer was dried overanhydrous magnesium sulfate. The solvent was then distilled away underreduced pressure, and a residue (320 mg) containing the title compoundwas obtained.

A peak of the bromomethyl group was observed at around δ 4.9 (ppm) in ¹HNMR (270 MHz, CD₃OD).

Compound 6c-3-4-1P4-Fluoromethyl-3-(2-fluoro-3-aminobenzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

THF (5.0 mL) was added to the residue (315 mg) containing4-bromomethyl-3-(2-fluoro-3-{[1-phenyl-meth-(Z)-ylidene]-amino}-benzyl)-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran(compound 6b-3-4-1P) obtained in the previous reaction. Potassiumfluoride (84.0 mg) and 18-crown-6 (381 mg) were added to the resultantsuspension while stirring at room temperature, and the suspension washeated under reflux for 2.5 hours. After cooling to room temperature,ethyl acetate and water were added thereto, and the mixture wasextracted. The resultant organic layer extraction liquid was washed withsaturated saline, and the organic layer was dried over anhydrousmagnesium sulfate. The solvent was distilled away under reducedpressure, ethyl acetate (3.0 mL) and 1N hydrochloric acid (3.0 mL) wereadded to the resultant residue, and the mixture was stirred at roomtemperature for 10 minutes. Ethyl acetate and saturated sodium hydrogencarbonate were then added, and the mixture was extracted. The resultantorganic layer extraction liquid was washed with saturated saline, andthe organic layer was dried over anhydrous magnesium sulfate. Thesolvent was distilled away under reduced pressure, and the resultantresidue was purified by silica gel chromatography (hexane:ethylacetate=4:1 to 1:1) to yield a mixture (20.6 mg) containing the titlecompound.

A peak of the fluoromethyl group was observed at around δ 5.5 (ppm) in¹H NMR (270 MHz, CDCI₃).

(General Process-7)

Next, manufacturing examples associated with General process-7previously mentioned will be explained.

Compound 7c-1-3OH Dimethylcarbamic acid6-chloro-4-(2-hydroxyethyl)-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

LiHMDS (57.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at−78° C. to a suspension of dimethylcarbamic acid6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester(compound 1g-1-3) (20.0 g, 48.0 mmol) in anhydrous THF (250 mL), and thereaction mixture was stirred at −78° C. for 30 minutes and at 0° C. for30 minutes. Paraformaldehyde (2.88 g, 96.0 mmol) was then added thereto,and the mixture was stirred at room temperature overnight. The reactionmixture was then poured into water and extracted twice with ethylacetate. The organic extract was washed with saturated saline and driedover magnesium sulfate. A crude solid was obtained by vacuumconcentration, and it was washed with ethyl acetate to yield the titlecompound (18.5 g, 86%) as a white powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.10 (m, 2H), 8.06 (s, 1H), 7.65 (d,J=8.1 Hz, 1H), 7.57 (t, J=8.1 Hz, 1H), 7.52 (s, 1H), 4.91 (t, J=5.4 Hz,1H), 4.16 (s, 2H), 3.63 (q, J=5.4 Hz, 2H), 3.14 (m, 2H), 3.12 (s, 3H),2.95 (s, 3H).

ESIMS m/z: 447 (M+H).

Compound 7d-1-3OH Dimethylcarbamic acid6-chloro-4-(2-hydroxyethyl)-3-(3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 7c-1-3OHwas used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.04 (s, 1H), 7.49 (s, 1H), 6.90 (t,J=8.0 Hz, 1H), 6.36 (m, 3H), 4.96 (s, 2H), 4.88 (t, J=5.4 Hz, 1H), 3.87(s, 2H), 3.60 (q, J=5.4 Hz, 2H), 3.11 (s, 3H), 3.04 (t, J=6.0 Hz, 2H),2.95 (s, 3H).

ESIMS m/z: 417 (M+H).

Compound 7c-1-1OH Dimethylcarbamic acid4-(2-hydroxyethyl)-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 7c-1-3OH, except that compound 1g-1-1was used instead of compound 1g-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.13 (d, 1H, J=1.8 Hz), 8.06 (dd, 1H,J=8.1, 1.4 Hz), 7.91 (d, 1H, J=8.7 Hz), 7.73 (d, 1H, J=8.3 Hz), 7.58 (t,1H, J=8.1 Hz), 7.27 (d, 1H, J=2.3 Hz), 7.20 (dd, 1H, J=8.7, 2.5 Hz),4.91 (t, 1H, J=5.6 Hz), 4.15 (s, 2H), 3.70 (m, 2H), 3.11 (m, 2H), 3.07(s, 3H), 2.95 (s, 3H).

ESIMS m/z: 413 (M+H).

Compound 7d-1-1OH Dimethylcarbamic acid4-(2-hydroxyethyl)-3-(3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 7c-1-1OHwas used instead of compound 1g-1-5.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 7.62 (d, 1H, J=8.7 Hz), 7.25-7.00 (m,3H), 6.70-6.42 (m, 3H), 4.00 (s, 2H), 3.71 (t, 2H, J=7.1 Hz), 3.20-3.10(s+t, 5H), 3.03 (s, 3H).

ESIMS m/z: 383 (M+H).

Compound 7f-1-3CO Dimethylcarbamic acid6-chloro-3-(3-nitrobenzyl)-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-ylester

LiHMDS (11.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at−78° C. to a suspension of dimethylcarbamic acid6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester(compound 1g-1-3) (4.0 g, 9.60 mmol) in anhydrous THF (100 mL), and themixture was stirred at −78° C. for 30 minutes and at 0° C. for 30minutes. Acetyl chloride (1.36 mL, 19.2 mmol) was then added thereto,and the mixture was stirred at room temperature for 1 hour. The reactionmixture was then poured into water and extracted with ethyl acetate. Theorganic extract was washed with saturated saline and dried overmagnesium sulfate. A crude solid was obtained by vacuum concentration,and purified by column chromatography (ethyl acetate:hexane=1:3) toyield the title compound (1.28 g, 29%) as a white powder.

¹H NMR (DMSO-d_(b), 270 MHz) δ (ppm): 8.12 (s, 1H), 8.05 (d, J=5.4 Hz,1H), 7.92 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.51(s, 1H), 4.44 (s, 2H), 4.07 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.27(s, 3H).

ESIMS m/z: 459 (M+H).

Compound 7g-1-3CO

Dimethylcarbamic acid6-chloro-3-(3-aminobenzyl)-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that compound 7f-1-3COwas used instead of compound 1g-1-5.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 7.89 (s, 1H), 7.53 (s, 1H), 6.88 (t,J=8.1 Hz, 1H), 6.37-6.32 (m, 3H), 5.76 (s, 2H), 4.96 (s, 2H), 3.76 (s,2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.23 (s, 3H).

ESIMS m/z: 429 (M+H).

Compound 7c-1-3MeOH Dimethylcarbamic acid6-chloro-4-(2-hydroxypropyl)-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Sodium borohydride (49 mg, 1.30 mmol) was added to a solution ofdimethylcarbamic acid6-chloro-3-(3-nitrobenzyl)-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-ylester (compound 7f-1-3CO) (300 mg, 0.65 mmol) in anhydrous THF (5.0 mL),and the mixture was stirred at 0° C. for 2 hours. The reaction mixturewas then poured into water and extracted with ethyl acetate. The organicextract was washed with saturated saline and dried over magnesiumsulfate, and the title compound (280 mg, 93%) was obtained as a paleyellow powder.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 8.12-8.05 (m, 3H), 7.71 (d, J=8.2 Hz,1H), 7.60-7.50 (m, 2H), 4.88 (d, J=5.4 Hz, 1H), 4.22 (d, J=14.8 Hz, 1H),4.11 (d, J=14.8 Hz, 1H), 3.86 (m, 1H), 3.11 (s, 3H), 3.00 (m, 2H), 2.95(s, 3H), 1.23 (d, J=5.5 Hz, 3H).

ESIMS m/z: 461 (M+H).

Compound 7f-1-1COOH{3-(3-Nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}aceticacid

The compound dimethylcarbamic acid4-(2-hydroxyethyl)-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester(compound 7c-1-1OH) was synthesized under the same conditions as in themanufacturing example for compound 7c-1-3OH, except that compound 1g-1-1was used instead of compound 1g-1-3.

Jones reagent (3.2 mL, 2.67 M, 8.58 mmol) was added at 0° C. to asolution of compound 7c-1-1OH (1.18 g, 2.86 mmol) in acetone (25 mL),and the mixture was stirred at room temperature for 30 minutes.2-Propanol was added slowly to the reaction mixture until the red colordisappeared, and it was then poured into water and extracted with ethylacetate. The organic extract was washed with water and dried overmagnesium sulfate. The title compound (865 mg, 71%) was obtained byvacuum concentration as a pale yellow powder.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 8.12 (s, 1H), 8.07 (d, J=8.2 Hz, 1H),7.86 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H),7.26 (d, J=2.1 Hz, 1H), 7.19 (dd, J=8.7, 2.2 Hz, 1H), 4.14 (s, 2H), 3.29(s, 2H), 3.07 (s, 3H), 2.93 (s, 3H).

ESIMS m/z: 427 (M+H).

Compound 7f-1-3 COOH(3-(3-Nitrobenzyl)-6-chloro-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl)aceticacid

The title compound was synthesized under the same conditions as in themanufacturing example for compound 7i-1-1COOH, except that compound7c-1-3OH was used instead of compound 7c-1-1OH.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.12 (s, 1H), 8.07 (d, 1H, J=5.4 Hz),8.03 (s, 1H), 7.71 (d, 2H, J=8.1 Hz), 7.57 (t, 1H, J=8.1 Hz), 7.50 (s,1H), 4.14 (s, 2H), 3.28 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 461 (M+H).

Compound 7f-1-1COOMe{3-(3-Nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}aceticacid methyl ester

Trimethylsilyl diazomethane (0.82 mL, 2.0 M in hexane) was added to asolution of{3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}aceticacid (compound 7f-1-1COOH) (350 mg, 0.82 mmol) in methanol (5.0mL)/dichloromethane (8.0 mL), and the mixture was stirred at roomtemperature for 10 minutes. Aacetic acid (2.0 mL) was added to thereaction mixture, and the title compound (338 mg, 94%) was obtained byvacuum concentration as a pale yellow powder.

¹H NMR (CDCl₃, 270 MHz) δ (ppm): 8.12 (s, 1H), 8.07 (d, J=8.2 Hz, 1H),7.76 (d, J=8.7 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H),7.22 (s, 1H), 7.19 (d, J=8.5 Hz, 1H), 4.24 (s, 2H), 4.16 (s, 2H), 3.50(s, 3H), 3.06 (s, 3H), 2.93 (s, 3H).

ESIMS m/z: 441 (M+H).

Compound 7f-1-3CONH2 Dimethylcarbamic acid3-(3-nitrobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-ylester

HODhbt (78 mg, 0.50 mmol) and WSC (91 mg, 0.50 mmol) were added to asolution of compound 7f-1-3COOH (185 mg, 0.40 mmol) in DMF (4.0 mL), andthe mixture was stirred at room temperature for 2 hours. NH₃ (0.33 M inTHE, 6.1 mL, 2.00 mmol) was added dropwise to the reaction mixture, andthe obtained mixture was stirred at room temperature for a day and anight. Water was then added to the reaction mixture, and extraction wasperformed with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate, and then concentratedunder reduced pressure to yield the title compound (170 mg, 93%) as awhite solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.19 (s, 1H), 8.06 (m, 1H), 7.98 (s,1H), 7.76-7.70 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.52 (s, 1H), 7.26 (s,1H), 4.13 (s, 2H), 3.96 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 460 (M+H).

Compound 7g-1-3CONH2 Dimethylcarbamic acid3-(3-aminobenzyl)-4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound7f-1-3CONH2 was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.00 (s, 1H), 7.68 (m, 1H), 7.56 (s,1H), 7.25 (m, 1H), 6.90 (t, 1H, J=8.1 Hz), 6.36 (m, 3H), 4.96 (s, 2H),3.83 (s, 2H), 3.83 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H).

ESIMS m/z: 430 (M+H).

Compound 7 g-1-3CONMe2 Dimethylcarbamic acid3-(3-aminobenzyl)-4-dimethylcarbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-ylester

The compound dimethylcarbamic acid3-(3-nitrobenzyl)-4-dimethylcarbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-ylester (compound 7f-1-3CONMe2) was synthesized under the same conditionsas in the manufacturing example for compound 7f-1-3CONH2, except thatdimethylamine was used instead of ammonia.

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound7f-1-3CONMe2 was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.84 (s, 1H), 7.49 (s, 1H), 6.88 (m,1H), 6.37-6.33 (m, 3H), 4.93 (s, 2H), 4.05 (s, 2H), 3.75 (s, 2H), 3.10(s, 6H), 2.95 (s, 3H), 2.81 (s, 3H).

ESIMS m/z: 458 (M+H).

Compound 7c-1-3OMe Dimethylcarbamic acid6-chloro-4-methoxymethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

Potassium carbonate (279 mg, 2.01 mmol) was added to a solution ofdimethylcarbamic acid6-chloro-4-bromomethyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-ylester (compound 6b-1-3) (500 mg, 1.01 mmol) in THF (7.5 mL)/methanol(5.0 mL), and the mixture was stirred at room temperature for 2 hours.The reaction mixture was then poured into water and extracted with ethylacetate. The organic extract was washed with saturated saline and driedover magnesium sulfate. The solvent was distilled away by concentrationunder reduced pressure, and the resultant residue was purified by columnchromatography to yield the title compound (40 mg, 10%) as a whitesolid.

¹H NMR (270 MHz, CDCl₃) δ (ppm): 8.14 (s, 1H), 8.05 (d, 1H, J=8.1 Hz),7.95 (s, 1H), 7.70 (d, 1H, J=8.0 Hz), 7.47 (t, 1H, J=8.1 Hz), 7.27 (s,1H), 4.71 (s, 2H), 4.13 (s, 2H), 3.48 (s, 3H), 3,17 (s, 3H), 3.00 (s,3H).

ESIMS m/z: 447 (M+H).

Compound 7d-1-3OMe Dimethylcarbamic acid6-chloro-4-methoxymethyl-3-(3-aminobenzyl)-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound7c-1-3OMe was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.00 (s, 1H), 7.51 (s, 1H), 6.90 (t,1H, J=8.0 Hz), 6.38-6.34 (m, 3H), 4.98 (s, 2H), 4.71 (s, 2H), 3.90 (s,2H), 3.37 (s, 3H), 3.10 (s, 3H), 2.95 (s, 3H).

(General Process-8)

Next, manufacturing examples associated with General process-8previously mentioned will be explained.

Compound 8c-1 (2-Chloro-3-fluoropyridin-4-yl)-methanol

2-Chloro-3-fluoropyridine (1.51 mL, 14.9 mmol) was added under nitrogenatmosphere at −78° C. to a mixture of 2.0 M lithium diisopropylamide (inTHF) (7.44 mL, 14.9 mmol) and THY (24 mL), and the mixture was stirredat 0° C. for 2 hours. DMF (11.4 mL, 149 mmol) was added to the mixture,and the obtained mixture was stirred at 0° C. for additional 2 hours.Sodium borohydride (731 mg, 19.3 mmol) was then added thereto, and themixture was stirred at 0° C. for 1 hour. Water was then added to thereaction solution, which was then extracted with ethyl acetate. Thesolution was washed with 1N HCl, sodium hydrogen carbonate solution andsaturated saline. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled away under reduced pressure. Theresultant residue was purified by silica gel column chromatography toyield the title compound (1.4 g, 58%).

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 4.65 (2H, d, J=5.8 Hz), 5.70 (1H, t,J=5.8 Hz), 7.56 (1H, dd, J=4.6 Hz), 8.27 (1H, d, J=4.6 Hz).

ESI (LC/MS positive mode) m/z: 162 (M+H).

Compound 8c-24-(tert-Butyldimethylsilyloxymethyl)-2-chloro-3-fluoropyridine

A mixture of (2-chloro-3-fluoropyridin-4-yl)-methanol (200 mg, 1.24mmol), imidazole (253 mg, 3.72 mmol) and tert-butyldimethylchlorosilane(373 mg, 2.48 mmol) in DMF was stirred at room temperature for 2 hours.Methylene chloride was then added to the reaction solution, and thesolution was washed with saturated saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was distilled awayunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography to yield the title compound (31.9 mg, 93%).

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.12 (6H, s), 0.86 (9H, s), 4.87 (2H,s), 7.51 (1H, dd, J=4.9 Hz), 8.30 (1H, d, J=4.9 Hz).

ESI (LC/MS positive mode) m/z: 276 (M+H).

Compound 8c-3Benzhydrylidene-[4-(tert-butyldimethylsilyloxymethyl)-3-fluoropyridin-2-yl]-amine

A mixture of4-(tert-butyldimethylsilyloxymethyl)-2-chloro-3-fluoropyridine (30 mg,108 μmol), benzophenone imine (14 μL, 84 μmol),tris(dibenzylideneacetone)dipalladium(0) (7.7 mg, 8.4 μmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (15.7 mg, 25.3 μmol)and sodium tert-butoxide (10.4 mg, 108 μmol) in toluene (0.5 mL) wasstirred at 60° C. overnight. Ethyl acetate was then added to thereaction solution, and the solution was washed with sodium hydrogencarbonate solution and saturated saline. The organic layer was driedover anhydrous magnesium sulfate, and the solvent was distilled awayunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography to yield the title compound (27 mg, 60%).

¹H NMR (CD₃OD, 270 MHz) δ (ppm): 0.00 (6H, s), 0.86 (9H, s), 4.60 (2H,s), 5.42 (1H, s), 7.00-7.80 (11H, m), 7.97 (1H, d, J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 421 (M+H).

Compound 8c-4 [2-(Benzhydrylidene-amino)-3-fluoropyridin-4-yl]-methanol

A mixture ofbenzhydrylidene-[4-(tert-butyldimethylsilyloxymethyl)-3-fluoropyridin-2-yl]-amine(14 mg, 32 μmol) and tetrabutylammonium fluoride (1 mol/L in THF) (65μL, 65 μmol) in THF (0.5 mL) was stirred at room temperature for 30minutes. Ethyl acetate was then added to the reaction solution, and thesolution was washed with sodium hydrogen carbonate solution andsaturated saline. The organic layer was dried over anhydrous magnesiumsulfate, and the solvent was distilled away under reduced pressure. Theresultant residue was purified by silica gel column chromatography toyield the title compound.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 4.47 (2H, d, J=5.6 Hz), 5.47 (1H, t,J=5.6 Hz), 7.04-7.20 (3H, m), 7.25-7.40 (3H, m), 7.45-7.75 (5H, m), 8.04(1H, d, J=5.0 Hz).

ESI (LC/MS positive mode) m/z: 307 (M+H).

Compound 5t-0-16a2-[2-(Benzhydrylidene-amino)-3-fluoropyridin-4-ylmethyl]-3-oxobutanoicacid ethyl ester

A mixture of [2-(benzhydrylidene-amino)-3-fluoropyridin-4-yl]-methanol(compound 8c-4) (5 g, 16.3 mmol), methanesulfonyl chloride (1.52 mL,19.6 mmol) and lithium tert-butoxide (in THF) (18 mL, 18 mmol) in THF(40 mL) was stirred at 0° C. for 1 hour. The mixture was added to asolution of acetoacetic acid ethyl ester (4.16 mL, 32.7 mmol), lithiumtert-butoxide (in THF) (19.6 mL, 19.6 mmol) and NaI (2.5 g, 16.3 mmol)in THF (18 mL). The solution was stirred at 50° C. for 3 hours, 0.2NLiOH (in water) and ethyl acetate were added thereto, and the solutionwas washed with 0.2N LiOH (in water) and saturated saline. After dryingover anhydrous magnesium sulfate, the solvent was distilled away underreduced pressure to yield the title compound (6.98 g, quant.).

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 1.10 (3H, t, J=7.0 Hz), 2.13 (3H, s),2.90-3.05 (2H, m), 3.94 (1H, t, J=7.7 Hz), 4.05 (2H, q, J=7.0 Hz), 6.91(1H, dd, J=4.3 Hz), 7.05-7.15 (2H, m), 7.30-7.75 (8H, m), 7.93 (1H, d,J=4.3 Hz).

ESI (LC/MS positive mode) m/z: 419 (M+H).

Compound 5t-0-16Meb2-(2-Amino-3-fluoropyridin-4-ylmethyl)-3-oxopentanoic acid ethyl ester

The title compound was synthesized, by performing reaction under thesame conditions as in the manufacturing example for compound 5t-0-16a,except that ethylpropionyl acetate was used instead of acetoacetic acidethyl ester, and then performing deprotection using 3N HCl.

¹H NMR (DMSO-d₆, 270 MHz) δ (ppm): 0.91 (3H, t, J=7.3 Hz), 1.11 (3H, t,J=7.1 Hz), 2.50-2.61 (2H, m), 2.94-3.02 (2H, m), 3.98-4.12 (3H, m), 6.10(2H, s), 6.39 (1H, t, J=5.1 Hz), 7.61 (1H, d, J=5.1 Hz).

ESI (LC/MS positive mode) m/z: 269 (M+H).

Compound 5d-0-Me 7-Hydroxy-3,4-dimethyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1e-0-4, except that ethyl 2-methylacetoacetate was used instead of compound 1c-2.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.36 (s, 1H), 7.61 (d, 1H, J=8.7Hz), 6.79 (dd, 1H, J=8.7, 2.5 Hz), 6.68 (d, 1H, J=2.5 Hz), 2.34 (s, 3H),2.05 (s, 3H).

ESIMS m/z: 191 (M+H).

Compound 1h-3-Me 3,4-Dimethyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-3-3, except that7-hydroxy-3,4-dimethyl-2-oxo-2H-1-benzopyran (compound 5d-0-Me) was usedinstead of compound 1e-0-3.

¹H NMR (270 MHz, DMSO-d₆) δ: 7.89 (d, 1H, J=9.1 Hz), 7.45 (d, 1H, J=2.5Hz), 7.36-7.32 (m, 3H), 2.42 (s, 3H), 2.13 (s, 3H).

ESIMS m/z: 274 (M+H).

Compound 1h-3-CH2Br3-Bromomethyl-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

N-Bromosuccinimide (1.17 g, 6.59 mmol) and AIBN (45 mg, 0.27 mmol) wereadded to a solution of compound 1h-3-Me (1.50 g, 5.49 mmol) in carbontetrachloride (80 mL), and the mixture was stirred at 75° C. for 2hours. The solvent was distilled away by concentration under reducedpressure, and the resultant residue was purified by columnchromatography (ethyl acetate:hexane=1:2) to yield the title compound(1.25 g, 65%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.99 (d, 1H, J=8.7 Hz), 7.51 (d, 1H,J=2.5 Hz), 7.41 (d, 1H, J=2.5 Hz), 7.38 (m, 2H), 4.68 (s, 2H), 2.54 (s,3H).

ESIMS m/z: 354 (M+H).

Compound 1h-3-57PN-(2-(4-Methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran-3-ylmethoxy)phenyl)acetamide

o-Acetamidophenol (118 mg, 0.78 mmol) and potassium carbonate (118 mg,0.85 mmol) were added to a solution of compound 1h-3-CH2Br (250 mg, 0.71mmol) in THF (5.0 mL), and the mixture was stirred at 40° C. for 2hours. The reaction mixture was then poured into water, and extractionwas performed with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate, and then concentratedunder reduced pressure to yield a crude product. The residue waspurified by column chromatography (ethyl acetate:hexane=1:2) to yieldthe title compound (100 mg, 33%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.97 (s, 1H), 8.02 (d, 1H, J=8.7 Hz),7.97 (d, 1H, J=9.6 Hz), 7.53 (d, 1H, J=2.5 Hz), 7.40 (dd, 1H, J=8.9, 2.5Hz), 7.37 (s, 2H), 7.25 (d, 1H, J=6.8 Hz), 7.08 (t, 1H, J=8.2 Hz), 6.95(t, 1H, J=7.3 Hz), 5.10 (s, 2H), 2.56 (s, 3H), 2.04 (s, 3H).

ESIMS m/z: 423 (M+H).

Compound 1h-3-57 3-(2-Aminophenoxymethyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

Concentrated sulfuric acid was added to a solution of compound 1h-3-57P(85 mg, 0.20 mmol) in ethanol (3.0 mL), THF (3.0 mL) and water (0.5 mL),and the mixture was stirred at 75° C. for 3 hours. The reaction mixturewas then neutralized with saturated sodium hydrogen carbonate solutionand extracted with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate, and then concentratedunder reduced pressure to yield a crude product. The residue waspurified by preparative LCMS to yield the title compound (30 mg, 39%) asa pale yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.99 (d, 1H, J=8.9 Hz), 7.52 (m, 1H),7.41 (m, 1H), 7.38-7.35 (m, 3H), 6.96 (d, 1H, J=8.1 Hz), 6.70 (d, 1H,J=7.4 Hz), 6.63 (d, 1H, J=7.6 Hz), 6.52 (t, 1H, J=7.6 Hz), 5.02 (s, 2H),4.71 (s, 2H), 2.55 (s, 3H).

ESIMS m/z: 381 (M+H).

Compound 1j-3-57-23-(2-(Methylaminosulfonyl)aminophenoxymethyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-3-57 was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.41 (s, 1H), 8.02 (d, 1H, J=8.9 Hz),7.53 (d, 1H, J=2.3 Hz), 7.39 (m, 4H), 7.22 (dd, 1H, J=8.2, 1.2 Hz), 7.10(m, 2H), 6.94 (td, 1H, J=7.7, 1.3 Hz), 5.08 (s, 2H), 2.56 (s, 3H), 2.41(d, 3H, J=4.9 Hz).

ESIMS m/z: 474 (M+H).

Compound 1h-3-58PN-(3-((4-Methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran-3-ylmethyl)amino)phenyl)acetamide

m-Acetylaminoaniline (118 mg, 0.78 mmol) and potassium carbonate (118mg, 0.85 mmol) were added to a solution of compound 1h-3-CH2Br (250 mg,0.71 mmol) in THF (5.0 mL), and the mixture was stirred at 75° C. for 3hours. The reaction mixture was then poured into water, and extractionwas performed with ethyl acetate. The organic extract was washed withsaturated saline and dried over magnesium sulfate, and then concentratedunder reduced pressure to yield a crude product. The residue waspurified by column chromatography (ethyl acetate:hexane=1:2) to yieldthe title compound (110 mg, 37%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.68 (s, 1H), 7.95 (d, 1H, J=8.9 Hz),7.49 (d, 1H, J=2.5 Hz), 7.39-7.34 (m, 3H), 7.02 (s, 1H), 6.97 (d, 1H,J=7.9 Hz), 6.73 (d, 1H, J=7.6 Hz), 6.33 (d, 1H, J=8.2 Hz), 5.72 (t, 1H,J=4.9 Hz), 4.12 (d, 2H, J=4.9 Hz), 2.51 (s, 3H).

ESIMS m/z: 422 (M+H).

Compound 1h-3-583-((3-Aminophenylamino)methyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

Concentrated sulfuric acid (0.5 mL) was added to a solution of compound1h-3-58P (92 mg, 0.218 mmol) in ethanol (4.0 mL), THF (4.0 mL) and water(1.0 mL), and the mixture was stirred at 75° C. for 2 hours. Thereaction mixture was then neutralized with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extractwas washed with saturated saline and dried over magnesium sulfate, andthen concentrated under reduced pressure to yield a crude product. Theresidue was purified by preparative LCMS to yield the title compound (38mg, 46%) as a pale yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.94 (d, 1H, J=8.9 Hz), 7.49 (d, 1H,J=2.6 Hz), 7.38-7.34 (m, 3H), 6.73 (t, 1H, J=7.4 Hz), 5.88-5.84 (m, 3H),5.29 (t, 1H, J=5.3 Hz), 4.74 (s, 2H), 4.08 (d, 2H, J=5.3 Hz), 2.50 (s,3H).

ESIMS m/z: 380 (M+H).

Compound 1j-3-58-23-((3-(Methylaminosulfonyl)aminophenylamino)methyl)-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-3-58 was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.40 (s, 1H), 7.95 (d, 1H, J=8.7 Hz),7.50 (d, 1H, J=2.5 Hz), 7.38-7.35 (m, 3H), 7.11 (q, 1H, J=4.9 Hz), 6.98(5, 1H, J=7.9 Hz), 6.48-6.42 (m, 2H), 6.33 (d, 1H, J=7.1 Hz), 5.71 (d,1H, J=4.5 Hz), 4.12 (d, 2H, J=4.8 Hz), 2.51 (s, 3H), 2.45 (d, 3H, J=4.8Hz).

ESIMS m/z: 473 (M+H).

Compound 1e-0-NAcN-(7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl)acetamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1e-0-4, except that2-acetylamino-3-oxobutyrie acid ethyl ester (which is known in theliterature) was used instead of compound 1c-2.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.52 (s, 1H), 9.39 (s, 1H), 7.63 (d,1H, J=8.6 Hz), 6.84 (dd, 1H, J=8.5, 2.2 Hz), 6.73 (d, 1H, J=2.3 Hz),2.21 (s, 3H), 2.03 (s, 3H).

ESIMS m/z: 234 (M+H).

Compound 1e-0-NH2 7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-ylammoniumchloride

A 5 to 6N isopropanol hydrochloride solution (3.0 mL) was added to asolution of compound 1e-0-NAc (600 mg, 2.57 mmol) in THF (6.0 mL) andwater (0.6 mL), and the mixture was stirred at 80° C. for a day and anight. The mixture was then cooled to room temperature and concentratedunder reduced pressure to ⅓ volume. The precipitated solid was filteredout to yield the title compound (510 mg, 87%) as a faint orange solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.41 (d, 1H, J=8.7 Hz), 6.78 (dd, 1H,J=8.7, 2.5 Hz), 6.69 (d, 1H, J=2.3 Hz), 5.69 (brs, 3H), 2.19 (s, 3H).

ESIMS m/z: 192 (M−HCl+H).

Compound 1e-0-60N-(7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl)-2-nitrobenzenesulfonamide

Pyridine (0.18 mL, 2.20 mmol) and o-nitrobenzenesulfonyl chloride (487mg, 2.20 mmol) were added to a solution of compound 1e-0-NH2 (250 mg,1.10 mmol) in THF (5.0 mL), and the mixture was stirred at roomtemperature for a day and a night. Water was then added to the reactionmixture, extraction was performed with ethyl acetate, and the organicextract was washed with water and saturated saline. After drying overmagnesium sulfate, it was concentrated under reduced pressure to yield acrude product, which was then purified by column chromatography to yieldthe title compound (268 mg, 65%) as a yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.66 (s, 1H), 9.86 (s, 1H), 8.04 (m,1H), 7.94-7.83 (m, 3H), 7.67 (d, 1H, J=8.7 Hz), 6.86 (dd, 1H, J=8.8, 2.4Hz), 6.70 (d, 1H, J=2.8 Hz), 2.38 (s, 3H).

ESIMS m/z: 377 (M+H).

Compound 1g-1-60 Dimethylcarbamic acid3-(2-nitrobenzenesulfonylamino)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 1e-0-60was used instead of compound 1e-0-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.09 (s, 1H), 8.05 (m, 1H),7.86-7.80 (m, 4H), 7.26-7.20 (m, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.43(s, 3H).

ESIMS m/z: 448 (M+H).

Compound 1h-1-60 Dimethylcarbamic acid3-(2-aminobenzenesulfonylamino)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 4a-0-4, except that compound 1g-1-60was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 7.78 (d, 1H, J=8.7 Hz), 7.36 (d, 1H,J=8.4 Hz), 7.27-7.16 (m, 3H), 6.77 (d, 1H, J=8.4 Hz), 6.52 (t, 1H, J=7.5Hz), 3.06 (s, 3H), 2.93 (s, 3H), 2.32 (s, 3H).

ESIMS m/z: 418 (M+H).

Compound 1j-1-60-2 Dimethylcarbamic acid3-(2-(methylaminosulfonyl)aminobenzenesulfonylamino)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-5-2, except that compound1h-1-60 was used instead of compound 1h-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.18 (s, 1H), 8.99 (s, 1H), 7.79 (m,2H), 7.62 (d, 1H, J=8.7 Hz), 7.60-6.55 (m, 2H), 7.23-7.15 (m, 2H), 7.08(m, 1H), 3.06 (s, 3H), 2.93 (s, 3H), 2.47 (d, 3H, J=4.8 Hz), 2.40 (s,3H).

ESIMS m/z: 511 (M+H).

Compound 5d-0-CO2H7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylic acid

Pyridine (0.1 mL) and a 1N sodium hydroxide aqueous solution (20 mL)were added to 7-hydroxy-4-methyl-3-carbonitrile-2-oxo-2H-1-benzopyran(1.0 g, 4.97 mmol), and the mixture was stirred at room temperature fora day and a night. Water and a 6N hydrochloric acid aqueous solutionwere added to the reaction mixture (to pH 2), and the depositedprecipitate was filtered out. It was then washed with methanol to yieldthe title compound (577 mg, 53%).

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.74 (s, 1H), 7.72 (d, 1H, J=8.6Hz), 6.86 (d, 1H, J=8.6 Hz), 6.75 (s, 1H), 2.41 (s, 3H).

ESIMS m/z: 221 (M+H).

Compound 5d-0-56P7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylic acid(3-acetylaminophenyl)amide

HOBt (221 mg, 1.64 mmol) and WSC (313 mg, 1.64 mmol) were added to asolution of compound 5d-0-CO2H (300 mg, 1.36 mmol) in DMF (10 mL), andthe mixture was stirred at room temperature for 30 minutes.3-Aminoacetamide (225 mg, 1.50 mmol) was then added to the reactionmixture, and it was stirred at room temperature for 1.5 hours. Water wasthen added to the reaction mixture, and extraction was performed withethyl acetate. The organic extract was washed with saturated saline anddried over magnesium sulfate, and then concentrated under reducedpressure to yield the title compound (217 mg, 45%) as a pale yellowsolid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.73 (s, 1H), 10.45 (s, 1H), 9.99(s, 1H), 7.98 (s, 1H), 7.73 (d, 1H, J=8.7 Hz), 7.34 (m, 2H), 7.24 (t,1H, J=7.8 Hz), 6.88 (m, 2H), 6.77 (d, 1H, J=2.3 Hz), 2.39 (s, 3H), 2.04(s, 3H).

ESIMS m/z: 353 (M+H).

Compound 5d-0-56 7-Hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylicacid (3-aminophenyl)amide

Concentrated sulfuric acid (0.3 mL) was added to a suspension ofcompound 5d-0-56P (200 mg, 0.57 mmol) in ethanol (5.0 mL), THF (3.0 mL)and water (0.5 mL), and the mixture was stirred under reflux for 4hours. After cooling to room temperature, saturated sodium hydrogencarbonate solution was added, and extraction was performed withdichloromethane. The organic extract was dried over magnesium sulfateand then concentrated under reduced pressure to yield the title compound(143 mg, 81%) as a pale yellow solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.70 (s, 1H), 10.11 (s, 1H), 7.72(d, 1H, J=8.7 Hz), 7.01 (s, 1H), 6.95 (t, 1H, J=7.9 Hz), 6.86 (dd, 1H,J=8.4, 2.1 Hz), 6.77 (d, 1H, J=1.6 Hz), 6.71 (d, 1H, J=7.6 Hz), 6.30 (d,1H, J=5.8 Hz), 5.13 (brs, 2H), 2.38 (s, 3H).

ESIMS m/z: 311 (M+H).

Compound 1h-1-56 Dimethylcarbamic acid3-(3-aminophenylcarbamoyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-1-5, except that compound 5d-0-56was used instead of compound 1e-0-5.

¹H NMR (270 MHz, CD₃OD) δ (ppm): 8.13 (d, 1H, J=1.8 Hz), 7.92 (d, 1H,J=8.6 Hz), 7.49 (m, 2H), 7.24 m, 2H), 7.14 (dt, 1H, J=5.6, 1.3 Hz), 3.15(s, 3H), 3.02 (s, 3H), 2.55 (s, 3H).

ESIMS m/z: 382 (M+H).

Compound 1j-1-56-2 Dimethylcarbamic acid3-(3-(methylaminosulfonyl)aminophenylcarbamoyl)-4-methyl-2-oxo-2H-1-benzopyran-7-ylester

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that compound1h-1-56 was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 10.52 (s, 1H), 9.74 (s, 1H), 7.92 (d,1H, J=8.6 Hz), 7.47-7.42 (m, 2H), 7.34 (m, 1H), 7.30-7.22 (m, 3H), 6.97(d, 1H, J=7.4 Hz), 3.08 (s, 3H), 2.95 (s, 3H), 2.47 (d, 3H, J=4.0 Hz),2.45 (s, 3H).

ESIMS m/z: 475 (M+H).

2-Hydroxy-4-(pyrimidin-2-yloxy)benzoic acid

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that2,4-dihydroxybenzoic acid was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.69 (d, 2H, J=4.8 Hz), 7.85 (d, 1H,J=8.6 Hz), 7.33 (t, 1H, J=4.8 Hz), 6.81 (d, 1H, J=2.3 Hz), 6.77 (dd, 1H,J=8.6, 2.3 Hz).

ESIMS m/z: 233 (M+H).

3-Aminoethyl-2-fluoro-phenylamine

A solution of hexamethyltetramine (595 mg, 4.24 mmol) in chloroform (4.0mL) was heated under reflux, and a solution ofN-(3-bromomethyl-2-fluorophenyl)acetamide (950 mg, 3.86 mmol) inchloroform (8.0 mL) was then added thereto over a period of 40 minutes.The reaction mixture was further heated under reflux for 1 hour, andafter returning to room temperature, the white precipitate was filteredout and washed with chloroform. Methanol (24 mL) and concentratedhydrochloric acid (3.0 mL) were added to the white precipitate, and themixture was stirred at room temperature for 30 hours. After cooling to0° C., the reaction mixture was rendered alkaline with a 6N sodiumhydroxide aqueous solution (16.5 mL). It was then extracted withdichloromethane, and the organic extract was washed with saturatedsaline and dried over magnesium sulfate, and again washed with saturatedsaline. After drying over magnesium sulfate, the dried extract wasconcentrated under reduced pressure to yield a crude product, which wasthen purified by column chromatography to yield the title compound (337mg, 48%) as a brown solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 6.79 (t, 1H, J=7.6 Hz), 6.52-6.67 (m,2H), 4.98 (s, 2H).

ESIMS m/z: 141 (M+H).

Compound 1h-1-733-(3-Amino-2-fluorobenzyl)-7-(pyrimidin-2-yloxy)-benzo[e][1,3]oxazine-2,4-dione

Triethylamine (0.180 mL, 1.29 mmol) was added to a mixture of2-hydroxy-4-(pyrimidin-2-yloxy)benzoic acid (100 mg, 0.431 mmol) andchloroform (5.0 mL) at room temperature. The dark brown solution wascooled to 4° C., and methyl chloroformate (0.073 mL, 0.945 mmol) wasthen added thereto. The resulting light purple solution was stirred atroom temperature for 2.5 hours and concentrated under reduced pressure.It was then redissolved in chloroform (5.0 mL), and a solution oftriethylamine (0.120 mL, 0.861 mmol) and3-aminoethyl-2-fluoro-phenylamine (60.0 mg, 0.428 mmol) in chloroform(1.0 mL) was added thereto. The obtained mixture was stirred at roomtemperature for 64 hours. Water was then added to the reaction mixture,and extraction was performed with ethyl acetate. The organic extract waswashed with saturated saline and dried over magnesium sulfate, and thenagain washed with saturated saline. After drying over magnesium sulfate,it was concentrated under reduced pressure to yield a crude product,which was then purified by column chromatography to yield the titlecompound (25.8 mg, 16%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.72 (d, 2H, J=4.8 Hz), 8.05 (d, 1H,J=8.7 Hz), 7.47 (d, 1H, J=2.1 Hz), 7.38 (t, 1H, J=4.8 Hz), 7.35 (dd, 1H,J=8.7, 2.1 Hz), 6.78 (t, 1H, J=7.8 Hz), 6.67 (m, 1H), 6.45 (m, 1H), 5.15(s, 2H), 5.06 (s, 2H).

ESIMS m/z: 381 (M+H).

Compound 1j-1-73-23-(3-(Methylaminosulfonyl)-2-fluorobenzyl)-7-(pyrimidin-2-yloxy)-benzo[e][1,3]oxazine-2,4-dione

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that3-(3-amino-2-fluorobenzyl)-7-(pyrimidin-2-yloxy)-benzo[e][1,3]oxazine-2,4-dione(compound 1h-1-73) was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.44 (s, 1H), 8.71 (d, 2H, J=4.8 Hz),8.05 (d, 1H, J=8.7 Hz), 7.48 (d, 1H, J=2.2 Hz), 7.38 (t, 1H, J=4.8 Hz),7.29-7.36 (m, 2H), 7.25 (brq, 1H, J=5.1 Hz), 7.15 (m, 1H), 7.07 (t, 1H,J=7.9 Hz), 5.11 (s, 2H).

One of the methyl peaks was overlapped with the DMSO peak.

ESIMS m/z: 474 (M+H).

2-(3-Methyl-benzo[b]thiophen-6-yloxy)pyrimidine

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that 4-hydroxyphthalicacid was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.64 (d, 2H, J=4.5 Hz), 7.85 (d, 1H,J=2.1 Hz), 7.79 (d, 1H, J=8.7 Hz), 7.39 (d, 1H, J=1.1 Hz), 7.27 (t, 1H,J=4.8 Hz), 7.27 (dd, 1H, J=8.7, 2.1 Hz), 2.42 (s, 3H).

ESIMS m/z: 243 (M+H).

Compound 1g-2-742-(2-(2-Fluoro-3-nitrobenzyl)-3-methyl-benzo[b]thiophen-6-yloxy)pyrimidine

1-Bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zincchloride (71 mg, 0.520 mmol) were added to a solution of2-(3-methyl-benzo[b]thiophen-6-yloxy)pyrimidine (114 mg, 0.470 mmol) indichloromethane (1.0 mL), and the mixture was heated under reflux for17.5 hours. After returning to room temperature,1-bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zincchloride (71 mg, 0.520 mmol) were added thereto, and the mixture washeated under reflux for 23 hours. The reaction mixture was thenconcentrated under reduced pressure, and purified by columnchromatography to yield the title compound (67.5 mg, 36%) as a whitesolid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.63 (d, 2H, J=4.8 Hz), 8.05 (m, 1H),7.70-7.80 (m, 3H), 7.41 (m 1H), 7.26 (t, 1H, J=4.8 Hz), 7.24 (dd, 1H,J=8.5, 2.1 Hz), 4.40 (s, 2H), 2.41 (s, 3H).

ESIMS m/z: 366 (M+H).

Compound 1h-2-742-Fluoro-3-(3-methyl-6-(pyrimidin-2-yloxy)benzo[b]thiophen-2-ylmethyl)-phenylamine

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1h-1-5, except that2-(2-(2-fluoro-3-nitrobenzyl)-3-methyl-benzo[b]thiophen-6-yloxy)pyrimidine(compound 1g-2-74) was used instead of compound 1e-1-5.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.62 (d, 2H, J=4.8 Hz), 7.72 (m, 2H),7.26 (t, 1H, J=4.8 Hz), 7.33 (dd, 1H, J=8.7, 2.1 Hz), 6.79 (t, 1H, J=7.9Hz), 6.61 (m, 1H), 6.43 (m, 1H), 5.10 (s, 2H), 4.14 (s, 2H), 2.39 (s,3H).

ESIMS m/z: 366 (M+H).

Compound 1j-2-74-2[2-Fluoro-3-(3-methyl-6-(pyrimidin-2-yloxy)benzo[b]thiophen-2-ylmethyl)phenyl]-methylaminosulfonamide

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that2-fluoro-3-(3-methyl-6-(pyrimidin-2-yloxy)benzo[b]thiophen-2-ylmethyl)-phenylamine(compound 1h-2-74) was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 9.40 (s, 1H), 8.62 (d, 2H, J=4.8 Hz),7.72 (m, 2H), 7.33 (td, 1H, J=7.8, 2.0 Hz), 7.18-7.28 (m, 4H), 7.00-7.15(m, 2H), 4.25 (s, 2H), 2.39 (s, 3H).

One of the methyl peaks was overlapped with the DMSO peak.

ESIMS m/z: 459 (M+H).

4-(Pyrimidin-2-yloxy)phthalic acid

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1g-2-4, except that 4-hydroxyphthalicacid was used instead of compound 1e-0-4.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.68 (d, 2H, J=4.8 Hz), 7.78 (d, 1H,J=8.3 Hz), 7.39-7.46 (m, 2H), 7.32 (t, 1H, J=4.8 Hz).

ESIMS m/z: 261 (M+H).

Compound 1h-2-752-(3-Amino-2-fluorobenzyl)-5-(pyrimidin-2-yloxy)-isoindole-1,3-dione

3-Aminomethyl-2-fluoro-phenylamine (50.8 mg, 0.362 mmol) and imidazole(26.0 mg, 0.382 mmol) were added to a solution of4-(pyrimidin-2-yloxy)phthalic acid (94.1 mg, 0.362 mmol) in DMF (2.0mL), and the mixture was stirred in a Microwave at 300 W, 150° C. for 5minutes. Water was then added to the reaction mixture, extraction wasperformed with ethyl acetate, and the organic extract was washed withsaturated saline. After drying over magnesium sulfate, it wasconcentrated under reduced pressure to yield a crude product, which wasthen purified by column chromatography to yield the title compound (13.4mg, 10%) as a white solid.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.70 (d, 2H, J=4.8 Hz), 7.97 (d, 1H,J=8.2 Hz), 7.80 (d, 1H, J=2.2 Hz), 7.69 (dd, 1H, J=8.2, 2.2 Hz), 7.36(t, 1H, J=4.8 Hz), 6.79 (t, 1H, J=7.9 Hz), 6.66 (m, 1H), 6.40 (m, 1H),5.17 (s, 2H), 4.75 (s, 2H).

ESIMS m/z: 365 (M+H).

Compound 1j-2-75-22-(3-Methylaminosulfonyl)-2-fluorobenzyl)-5-(pyrimidin-2-yloxy)-isoindole-1,3-dione

The title compound was synthesized under the same conditions as in themanufacturing example for compound 1j-1-3-2, except that2-(3-amino-2-fluorobenzyl)-5-(pyrimidin-2-yloxy)-isoindole-1,3-dione(compound 1h-2-75) was used instead of compound 1h-1-3.

¹H NMR (270 MHz, DMSO-d₆) δ (ppm): 8.70 (d, 2H, J=4.8 Hz), 7.98 (d, 1H,J=7.9 Hz), 7.81 (d, 1H, J=2.0 Hz), 7.69 (dd, 1H, J=7.9, 2.0 Hz), 7.36(m, 2H), 7.24 (brq, 1H, J=5.1 Hz), 7.09 (m, 2H), 4.82 (s, 2H), 3.17 (d,1H, J=5.1 Hz).

ESIMS m/z: 458 (M+H).

(3-Acetylaminophenylsulfamoyl)acetic acid ethyl ester

Ethanol was added at 0° C. to a solution of chlorosulfonylacetylchloride (1.0 g, 5.7 mmol) in ether (6 mL), the mixture was stirred for2 hours, and the solvent was distilled away. N-(3-Aminophenyl)acetamide(0.89 g), triethylamine (1.2 mL) and tetrahydrofuran (10 mL) were addedthereto, and the obtained mixture was stirred at room temperatureovernight. It was then purified by silica gel chromatography (methylenechloride:methanol=50:1) to yield the title compound (0.77 g, 46%).

¹H-NMR (Bruker (ARX-300), 300 MHz, CDCl₃) δ (ppm): 7.49 (1H, bs), 7.44(1H, bs), 7.31 (1H, t, J=8.0 Hz), 7.19 (1H, bs), 7.06 (1H, d, J=8.0 Hz),6.94 (1H, bs), 4.28 (2H, q, J=7.2 Hz), 3.95 (2H, s), 2.18 (3H, s), 1.32(3H, t, J=7.2 Hz).

MS (ESI+) m/z: 301.11 (M+1).

Compound 5d-0-61P4-Methyl-3-(3-(acetylamino)phenylaminosulfonyl)-7-hydroxy-2-oxo-2H-1-benzopyran

(3-Acetylaminophenylsulfamoyl)acetic acid ethyl ester (280 mg, 0.93mmol), 2,4-dihydroxybenzaldehyde (516 mg) and piperidine (10 mg) wereadded to 9 mL of ethanol, and the mixture was heated under refluxovernight. It was then purified by silica gel chromatography (methylenechloride:methanol=30:1) to yield the title compound (304 mg, 87%).

¹H-NMR (Broker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 11.2 (1H, s), 10.4(1H, s), 9.89 (1H, bs), 8.71 (1H, s), 7.78 (1H, d, J=8.8 Hz), 7.45 (1H,bs), 7.22 (1H, d, J=8.0 Hz), 7.11 (1H, t, J 8.0 Hz), 6.86 (1H, dd,J=2.3, 8.0 Hz), 6.80 (1H, d, J=8.0 Hz), 6.74 (1H, s), 1.98 (3H, s).

MS (ESI+) m/z: 374.80 (M+1).

Compound 5d-0-614-Methyl-3-(3-aminophenylaminosulfonyl)-7-hydroxy-2-oxo-2H-1-benzopyran

The title compound was obtained using compound 5d-0-61P and 4equivalents of methanesulfonic acid under heated reflux in anethanol/water mixed solvent.

¹H-NMR (Broker (ARX-300), 300 MHz, DMSO-d₆) δ (ppm): 11.2 (1H, bs), 10.0(1H, s), 8.67 (1H, s), 7.79 (1H, d, J=8.8 Hz), 6.86 (1H, dd, J=2.3, 8.0Hz), 6.82 (1H, t, J=8.0 Hz), 6.74 (1H, s), 6.36 (1H, m), 6.30 (1H, d,J=8.0 Hz), 6.20 (1H, d, J=8.0 Hz), 5.15 (2H, bs).

MS (ESI+) m/z: 332.92 (M+1).

TESTING EXAMPLES Testing Example 1 Measurement of Cell ProliferationInhibitory Activity

The cell proliferation inhibitory activities of the compounds and saltsshown in Tables 1-1, 1-2 and Table 2 were measured as follows, using thehuman colon cancer cell line HCT116 (American Type Culture Collection,VA, USA). 2000 to 3000 cells per well of the human colon cancer cellline HCT116 was placed in a 96-well culture plate, a predeterminedconcentration (0.00038 μM, 0.00076 μM, 0.0015 μM, 0.0031 μM, 0.0061 μM,0.012 μM, 0.024 μM, 0.049 μM, 0.098 μM, 0.195 μM, 0.39 μM, 0.78 μM, 1.56μM, 3.13 μM, 6.25 μM, 12.5 μM, 25 μM or 50 μM) of the test substance wasadded thereto, and the mixture was then incubated at 37° C. under 5% CO₂environment for 4 days. On day 4 of incubation, the Cell Counting Kit-8solution (Dojindo Laboratories) was added, the absorbance (measurementwavelength: 450 nm; reference wavelength: 615 nm) was measured followingthe protocol attached to the kit, and the 50% proliferation inhibitoryconcentration (IC50) was calculated. The results are shown in Tables1-1, 1-2 and Table 2.

Testing Example 2 Calculation of AUC Value

The AUC (area under the blood concentration-time curve) values of thecompounds and salts shown in Table 2 (only compound 1j-2-16-2 is Nasalt; the others are free form) were calculated by administering thetest substance to an animal and measuring its concentration in plasma.As the animals, BALB/c (nu/nu) mice (4 to 6 weeks old) procured fromJapan Charles River Laboratories were used after a one-week tamingperiod. As for the test substances other than Comp. 1, 5 mg/mL of thesubstance solution was given at 0.2 mL/10 g body weight (dose of thetest substance: 100 mg/kg body weight). As for Comp. 1, 10 mg/mL of thesubstance solution was given at 0.2 mL/10 g body weight (dose of thetest substance: 200 mg/kg body weight).

Administration of the substance solution to a mouse was performedforcibly using an oral feeding tube. Blood was collected from the eyepit 15 minutes, 2 hours, 7 hours and 24 hours after administration ofthe substance solution, using a hematocrit tube treated with heparin.Paraoxon (final concentration: 1 mM) was added to the collected blood asa stabilizer, the mixture was centrifuged at 10000 rpm for 3 minutes,and plasma was separated. The plasma was stored in a freezer set to −80°C. until the time of measurement. The measurement was carried out asfollows. 100 μL of distilled water to which the internal standardsubstance (a structural homolog, concentration adjusted appropriatelydepending on the compound used) had been added was added to 5 μL of theplasma, and then, a measurement sample was prepared through solid phaseextraction processing using an Oasis HLB μElution Plate (Waters), andwas analyzed by LC/MS/MS. The plasma concentration was calculated usinga calibration curve prepared based on the ratio of standard substance tointernal standard substance in control plasma of mice. The AUC wascalculated from the data of plasma concentration of the drug by thetrapezoidal method using Microsoft Excel 2003 (Microsoft). The resultsare shown in Table 2.

Compounds or salts according to the present invention are shown inTables 1-1, 1-2 and Table 2 below using compound numbers as used in thisspecification. “Comp. 1” denotes a compound of example number 20-44described in International Publication WO 2002/008217, i.e., a compoundrepresented by formula (A) below. “Comp. 2” denotes a compound ofexample 2 described in International Publication WO 2002/008217, i.e., acompound represented by formula (B) below (dimethylcarbamic acid2-oxo-2H-3-benzyl-4-methyl-6-chloro-1-benzopyran-7-yl ester).

TABLE 1-1 Compound IC50 (μM) 1j-1-4-1 0.0176 1j-1-4-2 0.0093 1j-1-4-2F0.0106 1j-1-5-1 0.0083 1j-1-5-2 0.0029 1j-1-3-2 0.0041 1j-1-2-3 0.01201j-1-3-2F 0.0195 1j-1-7-1 0.0114 1j-1-7-2 0.0079 1j-1-8-2 0.02171j-1-9-2 0.0242 1j-1-21-2 0.0230 1j-1-23-2 0.0360 1o-1-3-2 0.02101o-1-3-3 0.0160

TABLE 1-2 Compound IC50 (μM) 1j-1-10-2 0.0319 1j-1-11-2 0.0183 1j-1-12-20.0064 1j-2-17-2 0.0211 1j-2-18-2 0.0059 1j-2-19-2 0.0178 1j-2-19-2Me0.0084 1j-3-4-1 0.0225 1j-3-4-2 0.0109 1j-3-20-2 0.0089 1j-3-12-2 0.01221j-3-19-2 0.0015 1j-3-44-2 0.0129 Comp. 1 0.1600 Comp. 2 1.3000

TABLE 2 Compound AUC (μM · h) IC50 (μM) 1j-1-13-2  313.6 0.2711 1j-2-4-1 811 0.1496 1j-2-4-2  425 0.0447 1j-2-4-2F  317 0.1654 1j-2-5-2  3440.0751 1j-2-12-2  252 0.2816 1j-2-16-2 3203 (*) 0.0408 1j-3-1-2  199.30.1636 1j-3-8-2  148.9 0.0968 1o-3-4-2  367 0.3253 Comp. 1  97.6 0.1600(*) Na salt was used.

As seen in Tables 1-1, 1-2 and Table 2, the compound or salt accordingto the present invention exhibited a markedly smaller IC50 value thanconventional compounds, or exhibited a sufficiently small IC50 value,and a larger AUC value than conventional compounds. This suggests thatthe compound or salt according to the present invention has markedlyhigh antitumor activity compared to conventional compounds, or that ithas sufficiently high antitumor activity that is equivalent to those ofconventional compounds, and exhibits higher systemic exposure thanconventional compounds.

From Testing examples 1 and 2, it has been revealed that the compound orpharmaceutically acceptable salt thereof according to the presentinvention is effective as a therapeutic agent for cell proliferativedisorders, particularly cancers.

INDUSTRIAL APPLICABILITY

The compound or pharmaceutically acceptable salt thereof, pharmaceuticalcomposition, and therapeutic agent for a cell proliferative disorderaccording to the present invention can be used for treatment of cellproliferative disorders, particularly cancers.

1. A compound represented by general formula (11) below or a pharmaceutically acceptable salt thereof:

wherein: G¹, G², and G⁸ are each independently —N═, —CR¹═ or —C(-G⁹-X)═; G³ is —CR¹═; one from among G¹, G², and G⁸ is —C(-G⁹-X)═; X is a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally be substituted with a group selected from a halogen atom, a hydroxy group, a cyano group and —NR⁵⁶R⁵⁷), an aryl group, a heterocyclic group, R³¹CS—, R³¹CO—, R³³R³⁴NCS—, R³³R³⁴NC═NH—, R³R⁴NCO— or R³³R³⁴NCO₂—; G⁹ is a single bond, an oxygen atom, a sulfur atom, —(CR³⁵R³⁶)_(l)— (where l represents an integer of 1 to 3) or —NR³⁷—; Ring G⁶ is a divalent 6-membered aryl group, A is a group represented by general formula (2) below or a group represented by general formula (3) below:

G⁴ is an oxygen atom, a sulfur atom, —NR³⁸— or —CR⁴⁰R⁴¹—; G⁵ is two hydrogen atoms, or an oxygen atom, a sulfur atom or ═CH₂; G⁷ is CH₂; R¹ is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally be substituted with a group selected from a halogen atom, a hydroxy group and —NR⁴⁶R⁴⁷), a C₂₋₇ alkenyl group, a carbamoyl group or a C₂₋₇ alkynyl group (where the C₂₋₇ alkynyl group may optionally be substituted with a C₁₋₄ acyl group); when G² or G³ is —CR¹═, G⁸ is —C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; when G¹ or G⁸ is —CR¹═, G² is —C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—; or when G² is —CR¹═, G¹ is —C(-G⁹-X)═, and X is R³R⁴NCO—, R³³R³⁴NC═NH— or R³³R³⁴NCS—, R¹ may form a single bond or —CH₂— together with R⁴ or R³⁴; R² is a hydroxy group, a C₁₋₆ alkoxy group, —NR⁴⁸R^(49 or a C) ₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally be substituted with a group selected from a halogen atom, a hydroxy group, a C₁-₆ alkoxy group, a formyl group, —CO₂R⁵⁰ and —CO₂NR⁵¹R⁵²); R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, R³¹, R⁴⁶ and R⁴⁷ are each independently a hydrogen atom, a C₁₋₆ alkoxy group, a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally be substituted with a group selected from a cyano group, a halogen atom, a hydroxy group, a C₁₋₆ alkoxy group, —NR¹³R¹⁴, —CONR²⁸R²⁹ and an aryl group); R³³ and R³⁴ are each independently a hydrogen atom, a C₁₋₆ alkyl group or an aryl group; the combination of R³ and R⁴, combination of R⁶ and R⁷, combination of R⁹ and R¹⁰, combination of R³³ and R³⁴, and combination of R⁴⁶ and R⁴⁷ may form, together with the nitrogen atom to which they are bonded, a 4- to 6-membered heterocyclic group having at least one nitrogen atom (where the heterocyclic group may optionally be fused with a benzene ring); one R³⁵ group and one R³⁶ group are each independently a hydrogen atom, a halogen atom or a C₁₋₆ alkyl group; R¹³, R¹⁴, R⁵⁶ and R⁵⁷ are each independently a hydrogen atom, a C₁₋₆ alkyl group, —COR³² or —CO₂R³²; and R⁵, R⁸, R²⁸, R²⁹, R³², R³⁷, R³⁸, R⁴⁰, R⁴¹, R⁴⁸, R⁴⁹, R⁵⁰, R⁵¹, and R⁵² are each independently a hydrogen atom or a C₁₋₆ alkyl group.
 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by general formula (11) is a compound represented by general formula (1) below:

wherein: X is a heteroaryl group or R³R⁴NCO—; Y¹ and Y² are each independently —CR¹¹═; Y³ and Y⁴ may be the same or different, and are each —CR¹²═; A is a group represented by general formula (2) below or a group represented by general formula (3) below:

R¹ is a hydrogen atom, a halogen atom, a cyano group, a C₁₋₆ alkyl group, a C₂₋₇ alkenyl group, a carbamoyl group or a C₂₋₇ alkynyl group (where the C₂₋₇ alkynyl group may optionally be substituted with a C₁₋₄ acyl group); R² is a C₁₋₆ alkyl group optionally substituted with a halogen atom; R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ are each independently a hydrogen atom, a C₁₋₆ alkoxy group, a C₃₋₈ cycloalkyl group or a C₁₋₆ alkyl group (where the C₁₋₆ alkyl group may optionally be substituted with a group selected from a cyano group, a halogen atom, a hydroxy group, a C₁₋₆ alkoxy group and —NR¹³R¹⁴); the combination of R³ and R⁴, combination of R⁶ and R⁷, and combination of R⁹ and R¹⁰ may form, together with the nitrogen atom to which they are bonded, a 4- to 6-membered heterocyclic group having at least one nitrogen atom; R⁵, R⁸, R¹³ and R¹⁴ are each independently a hydrogen atom or a C₁₋₆ alkyl group; R¹¹ is a hydrogen atom, a halogen atom, a C₁₋₆ alkyl group, a C₁₋₄ acyl group, a C₁₋₄ acyloxy group or —NR¹⁵R¹⁶; R¹² is a hydrogen atom, a halogen atom or a C₁₋₆ alkyl group; and R¹⁵ and R¹⁶ are each independently a hydrogen atom or a C₁₋₄ acyl group.
 3. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R¹ is a hydrogen atom, a halogen atom or a C₁₋₆ alkyl group.
 4. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R⁵ or R⁸ is a hydrogen atom.
 5. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ are each independently a hydrogen atom or a C₁₋₆ alkyl group.
 6. The compound or pharmaceutically acceptable salt thereof according to claim 2, wherein X is a thiazol-2-yl group, a pyrimidin-2-yl group, a 2-pyridyl group or R³R⁴NCO— (where R³ and R⁴ have the same definitions as above). 7-9. (canceled)
 10. The compound or pharmaceutically acceptable salt thereof according to claim 2, which is selected from: dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-{3-(aminosulfonyl)aminobenzyl}-6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-aminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro -2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran, 3-{2-chloro-3-(aminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-fluoro-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-iodo-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-methyl-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-cyano-4-methyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylamino-2-fluoro-benzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylaminobenzyl)-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylaminosulfonylaminobenzyl)-6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 6-chloro-4-fluoromethyl-3-{3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-6-fluoro-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-fluoromethyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-chloro-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(thiazol-2-yloxy)-6-methyl-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 6-chloro-4-methyl-3-{3-(dimethylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester, 3-{2-fluoro-3-(dimethylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 3-(3-(N-(2-cyanoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-hydroxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-methoxyethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-(2-aminoethyl)sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride, dimethylcarbamic acid 3-(3-(N—(N′-methyl-2-aminoethyl)methylsulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride, dimethylcarbamic acid 3-(3-(N-2,2,2-trifluoroethyl-sulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-(N-methoxysulfamoyl)aminobenzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-carbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, dimethylcarbamic acid 3-(3-methylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, 2-{2-fluoro-3-[4-methyl-2-oxo-7-(pyrimidin-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide, dimethylcarbamic acid 3-(3-dimethylcarbamoylmethanesulfonylamino-benzyl)-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, 2-{2-fluoro-3-[4-methyl-2-oxo-7-(thiazol-2-yloxy)-2H-1-benzopyran-3-ylmethyl]phenylsulfamoyl}-N-methyl-acetamide, 3-{2-methyl-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-fluoropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(4-chloropyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(2,4-dimethoxypyrimidin-6-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(benzothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-(5-bromothiazol-2-yloxy)-2-oxo-2H-1-benzopyran, dimethylcarbamic acid 6-fluoro-4-methyl-3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-2-oxo-2H-1-benzopyran-7-yl ester.
 11. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 12-13. (canceled)
 14. The compound or pharmaceutically acceptable salt thereof according to claim 2, which is 3-{2-fluoro-3-(methylaminosulfonyl)aminobenzyl}-4-methyl-7-pyrimidin-2-yloxy)-2-oxo-2H-1-benzopyran. 